Pyrimidine compounds as serotonin receptor modulators

ABSTRACT

Certain pyrimidine-containing compounds are serotonin receptor modulators useful in the treatment of serotonin-mediated diseases.

RELATED APPLICATIONS

The present application claims the benefit under 35 U.S.C. §119(e) ofprovisional application Ser. No. 60/705,719, filed on Aug. 4, 2006,which is incorporated herein in its entirety.

FIELD OF THE INVENTION

There is provided by the present invention compounds that are serotoninreceptor modulators. More particularly, there is provided by the presentinvention pyrimidine compounds that are serotonin receptor modulatorsuseful for the treatment of disease states mediated by serotoninreceptor activity.

BACKGROUND OF THE INVENTION

Serotonin(5-hydroxytryptamine, 5-HT) is a major neurotransmittereliciting effects via a multiplicity of receptors. To date, at leastfifteen different 5-HT receptors have been identified, largely as theresult of cloning cDNA's, and these receptors have been grouped intoseven families (5-HT₁ through 5-HT₇) (Hoyer, D. et al. Pharmacol.Biochem. Behav. 2002, 71, 533-554). Fourteen of the fifteen cloned 5-HTreceptors are expressed in the brain. 5-HT is implicated in many diseasestates, particularly conditions of the central nervous system including;depression, anxiety, schizophrenia, eating disorders, obsessivecompulsive disorder, learning and memory dysfunction, migraine, chronicpain, sensory perception, motor activity, temperature regulation,nociception, sexual behavior, hormone secretion, and cognition. Theidentification of multiple 5-HT receptors has provided the opportunityto characterize existing therapeutic agents thought to act via theserotonergic system. Consequently, this has led to the realization thatmany drugs have non-selective properties (Roth, B. L. et al.Neuroscientist 2000, 6(4), 252-262). For example, the antipsychoticdrugs, clozapine, chlorpromazine, haloperidol and olanzapine exhibitaffinities for multiple serotonin receptors in addition to otherfamilies of receptors. Similar behavior has been noted forantidepressants, including imipramine, nortriptaline, fluoxetine andsertraline. Similarly, the anti-migraine agent sumatriptan exhibits highaffinity for several serotonin receptors. While the lack of selectivityoften contributes to a favorable therapeutic outcome, it can also causeundesirable and dose-limiting side effects (Stahl, S. M. EssentialPsychopharmacology, 2^(nd) ed., Cambridge University Press, Cambridge,U.K., 2000). Thus, the inhibition of serotonin and norepinephrine uptaketogether with 5-HT₂ receptor blockade is responsible for the therapeuticeffects of the tricyclic antidepressants. In contrast, their blockade ofhistamine H₁, muscarinic and alpha-adrenergic receptors can lead tosedation, blurred vision and orthostatic hypertension respectively.Likewise, the atypical antipsychotics, including olanzapine andclozapine, are considered to have positive therapeutic effectsattributable to their actions at 5-HT₂, D₂ and 5-HT₇ receptors.Conversely, their side effect liability is due to their affinities for arange of dopaminergic, serotonergic and adrenergic receptors.

More selective ligands therefore have the potential to ameliorateuntoward pharmacologies and provide novel therapies. More importantlythe ability to obtain compounds with known receptor selectivitiesaffords the prospect to target multiple therapeutic mechanisms andimprove clinical responses with a single drug.

4-Phenyltetrahydropyrido[4,3-d]pyrimidines with utility in the treatmentof gastrointestinal diseases have been described in U.S. Pat. No.5,137,890 (Sanfilippo et al.):

The features and advantages of the invention are apparent to one ofordinary skill in the art. Based on this disclosure, including thesummary, detailed description, background, examples, and claims, one ofordinary skill in the art will be able to make modifications andadaptations to various conditions and usages. Publications describedherein are incorporated by reference in their entirety.

Described herein is a series of pyrimidine compounds with the ability tomodulate the activity of serotonin receptors.

SUMMARY OF THE INVENTION

The invention features a compound of Formulae (I) or (II):

wherein

-   m is 1, 2, or 3;-   n is 1, 2, or 3;-   where when m and n are both present, m+n is greater than or equal to    2, and is less than or equal to 4;-   R^(a) and R^(b) are independently —H, —C₁₋₇alkyl, or    —C₃₋₇cycloalkyl, or R^(a) and R^(b) taken together with the nitrogen    of attachment form piperidinyl, pyrrolidinyl, morpholinyl,    thiomorpholinyl, or piperazinyl, where each R^(a) and R^(b) is    optionally and independently substituted with —C₁₋₄alkyl;-   q is 0 or 1;-   A is >NR¹, >CHNR^(c)R^(d), >CHOH, or —CH₂—, wherein    -   R¹ is selected from the group consisting of —H, —C₁₋₇alkyl,        —C₃₋₇cycloalkyl, and benzyl, where each alkyl, cycloalkyl, or        benzyl is optionally mono-, di-, or tri-substituted with R^(e);        -   R^(e) is selected from the group consisting of —C₁₋₄alkyl,            —C₂₋₄alkenyl, —C₂₋₄alkynyl, —C₃₋₆cycloalkyl, halo, —CF₃,            —OH, —OC₁₋₄alkyl, —OCF₃, —N(R^(f))R^(g) (wherein R^(f) and            R^(g) are independently —H or —C₁₋₄alkyl, or R^(f) and R^(g)            taken together with the nitrogen of attachment form            piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, or            piperazinyl), —C(O)N(R^(f))R^(g), —N(R^(h))C(O)R^(h),            —N(R^(h))SO₂C₁₋₇alkyl (wherein R^(h) is —H or —C₁₋₄alkyl, or            two R^(h) in the same substituent taken together with the            amide of attachment form an otherwise aliphatic 4- to            6-membered ring), —S(O)₀₋₂—C₁₋₄alkyl, —SO₂N(R^(f))R^(g),            —SCF₃, —C(O)C₁₋₄alkyl, —CN, —COOH, and —COOC₁₋₄alkyl;    -   R^(c) and R^(d) are independently selected from the group        consisting of —H, —C₁₋₇alkyl, —C₃₋₇alkenyl, —C₃₋₇alkynyl,        —C₃₋₇cycloalkyl, —C₁₋₇alkylC₃₋₇cycloalkyl, and        —C₃₋₇cycloalkylC₁₋₇alkyl, or R^(c) and R^(d) taken together with        the nitrogen of attachment form piperidinyl, pyrrolidinyl,        morpholinyl, thiomorpholinyl, or piperazinyl, where each R^(c)        and R^(d) is optionally and independently substituted with        R^(e);-   R³ is —C₁₋₄alkyl, —C₁₋₄alkenyl, or benzyl, each optionally    substituted with —C₁₋₃alkyl, —OH, or halo, or two R³ substituents    taken together form C₂₋₅alkylene optionally substituted with    —C₁₋₃alkyl, —OH, or halo;-   r is 0 or is an integer less than or equal to m+n+1;-   Ar is an aryl or heteroaryl ring selected from the group consisting    of:    -   a) phenyl, optionally mono-, di-, or tri-substituted with R¹ or        di-substituted on adjacent carbons with —OC₁₋₄alkyleneO—,        —(CH₂)₂₋₃NH—, —(CH₂)₁₋₂NH(CH₂)—, —(CH₂)₂₋₃N(C₁₋₄alkyl)-, or        —(CH₂)₁₋₂N(C₁₋₄alkyl)(CH₂)—;        -   R^(i) is selected from the group consisting of —C₁₋₇alkyl,            —C₂₋₇alkenyl, —C₂₋₇alkynyl, —C₃₋₇cycloalkyl, halo, —CF₃,            —OH, —OC₁₋₇alkyl, —OCF₃, —OC₃₋₇alkenyl, —OC₃₋₇alkynyl,            —N(R^(i))R^(k) (wherein R^(i) and R^(k) are independently —H            or —C₁₋₄alkyl), —C(O)N(R^(i))R^(k), —N(R^(i))C(O)R^(k),            —N(R^(j))SO₂C₁₋₆alkyl, —S(O)₀₋₂—C₁₋₆alkyl,            —SO₂N(R^(i))R^(k), —SCF₃, —C(O)C₁₋₆alkyl, —NO₂, —CN, —COOH,            and —COOC₁₋₇alkyl;    -   b) a monocyclic aromatic hydrocarbon group having five ring        atoms, having a carbon atom which is the point of attachment,        having one carbon atom replaced by >O, >S, >NH, or        >N(C₁₋₄alkyl), having up to two additional carbon atoms        optionally replaced by —N═, optionally mono- or di-substituted        with R^(i);    -   c) a monocyclic aromatic hydrocarbon group having six ring        atoms, having a carbon atom which is the point of attachment,        having one or two carbon atoms replaced by —N═, optionally mono-        or di-substituted with R^(i); and    -   d) phenyl or pyridyl, substituted with a substituent selected        from the group consisting of phenyl, phenoxy, pyridyl,        thiophenyl, oxazolyl, and tetrazolyl, where the resultant        substituted moiety is optionally further mono-, di-, or        tri-substituted with R^(i);-   ALK is a branched or unbranched C₁₋₇alkylene, C₂₋₇alkenylene,    C₂₋₇alkynylene, C₃₋₇cycloalkylene, or C₃₋₇cycloalkenylene,    optionally mono-, di-, or tri-substituted with R^(m);    -   R^(m) is selected from the group consisting of halo, —CF₃, —OH,        —OC₁₋₇alkyl, —OC₃₋₇cycloalkyl, —OCF₃, —N(R^(p))R^(s) (wherein        R^(p) and R^(s) are independently —H or —C₁₋₇alkyl),        —C(O)N(R^(p))R^(s), —N(R^(t))C(O)R^(t), —N(R^(t))SO₂C₁₋₆alkyl        (wherein R^(t) is —H or —C₁₋₇alkyl), —S(O)₀₋₂—C₁₋₆alkyl,        —SO₂N(R^(p))R^(s), —SCF₃, —CN, —NO₂, —C(O)C₁₋₇alkyl, —COOH, and        —COOC₁₋₇alkyl;-   CYC is —H or is a ring system selected from the group consisting of:    -   i) phenyl, optionally mono-, di-, or tri-substituted with R^(u)        or di-substituted on adjacent carbons with —OC₁₋₄alkyleneO—,        —(CH₂)₂₋₃NH—, —(CH₂)₁₋₂NH(CH₂)—, —(CH₂)₂₋₃N(C₁₋₄alkyl)-, or        —(CH₂)₁₋₂N(C₁₋₄alkyl)(CH₂)—;        -   R^(u) is selected from the group consisting of —C₁₋₇alkyl,            —C₃₋₇cycloalkyl, phenyl, benzyl, halo, —CF₃, —OH,            —OC₁₋₇alkyl, —OC₃₋₇cycloalkyl, —Ophenyl, —Obenzyl, —OCF₃,            —N(R^(v))R^(w) (wherein R^(v) and R^(w) are independently —H            or —C₁₋₇alkyl, or R^(v) and R^(w) taken together with the            nitrogen of attachment form piperidinyl, pyrrolidinyl,            morpholinyl, thiomorpholinyl, or piperazinyl, where each            R^(v) and R^(w) is optionally and independently substituted            with —OH or —C₁₋₇alkyl), —C(O)N(R^(v))R^(w),            —N(R^(x))C(O)R^(x), —N(R^(x))SO₂C₁₋₆alkyl (wherein R^(x) is            —H or —C₁₋₇alkyl, or two R^(x) in the same substituent taken            together with the amide of attachment form an otherwise            aliphatic 4- to 6-membered ring), —N—(SO₂C₁₋₆alkyl)₂,            —S(O)₀₋₂—C₁₋₆alkyl, —SO₂N(R^(v))R^(w), —SCF₃,            —C(O)C₁₋₆alkyl, —NO₂, —CN, —COOH, and —COOC₁₋₇alkyl;    -   ii) a monocyclic aromatic hydrocarbon group having five ring        atoms, having a carbon atom which is the point of attachment,        having one carbon atom replaced by >O, >S, >NH, or        >N(C₁₋₄alkyl), having up to one additional carbon atoms        optionally replaced by —N═, optionally mono- or di-substituted        with R^(u);    -   iii) a monocyclic aromatic hydrocarbon group having six ring        atoms, having a carbon atom which is the point of attachment,        having one or two carbon atoms replaced by —N═, optionally mono-        or di-substituted with R^(u); and    -   iv) a non-aromatic heterocyclic ring having 4 to 8 members, said        ring having 0, 1, or 2 non-adjacent heteroatom members selected        from the group consisting of O, S, —N═, >NH, and >N(C₁₋₄alkyl),        having 0, 1, or 2 double bonds, having 0, 1, or 2 carbon members        which is a carbonyl, optionally having one carbon member which        forms a bridge, having 0 to 5 substituents R^(u), and where when        q is 0, said ring has a carbon atom which is the point of        attachment;-   and enantiomers, diastereomers, hydrates, solvates, and    pharmaceutically acceptable salts, esters and amides thereof;-   with the proviso that in Formula (I):    -   (a) when ALK is methylene, ethylene, propylene, or isopropylene,        CYC is —H, Ar is phenyl or mono-substituted phenyl, m is 2, n is        1, and A is >NR¹, then R¹ is not —C₁₋₄alkyl or benzyl;    -   (b) when q is 0, CYC is phenyl, Ar is phenyl or 3-chlorophenyl,        m is 2, and n is 1, then A is not unsubstituted —CH₂—; and    -   (c) when q is 0, CYC is 2-pyridyl, Ar is 2-pyridyl, m is 2, and        n is 1, then A is not unsubstituted —CH₂—.

Isomeric forms of the compounds of Formulae (I) and (II) and of theirpharmaceutically acceptable salts, esters, and amides, are encompassedwithin the present invention, and reference herein to one of suchisomeric forms is meant to refer to at least one of such isomeric forms.One of ordinary skill in the art will recognize that compounds accordingto this invention may exist, for example in a single isomeric formwhereas other compounds may exist in the form of a regioisomericmixture.

The present invention provides methods of treating or preventingdiseases and conditions mediated by the serotonin receptors,particularly, 5-HT₇ and/or 5-HT₂ receptor subtypes.

The invention also features pharmaceutical compositions containing suchcompounds and methods of using such compositions in the treatment orprevention of disease states mediated by the serotonin receptors,particularly, 5-HT₇ and/or 5-HT₂ receptor subtypes.

Compounds of the present invention are useful in combination with othertherapeutic agents as a combination therapy method, including use incombination with selective serotonin reuptake inhibitors (SSRIs),anti-psychotics, norepinephrine reuptake inhibitors (NRIs), sedatives,monoamine oxidase inhibitors (MAOs), or tricyclic antidepressants(TCAs).

Additional features and advantages of the invention will become apparentfrom the detailed description and examples below, and the appendedclaims.

DETAILED DESCRIPTION

Particular preferred compounds of the invention comprise a compound ofFormula (I) or (II), or an enantiomer, diastereomer, hydrate, solvatethereof, or a pharmaceutically acceptable salt, amide or ester thereof,wherein m, n, R^(a), R^(b), q, A, R³, r, Ar, ALK, and CYC have any ofthe meanings defined hereinabove and equivalents thereof, or at leastone of the following assignments and equivalents thereof. Suchassignments may be used where appropriate with any of the definitions,claims or embodiments defined herein:

Preferably, m is 1 and n is 1.

Preferably, m is 1 and n is 2.

Preferably, m is 2 and n is 1.

Preferably, m is 2 and n is 2.

Preferably, m is 1 and n is 3.

Preferably, m is 3 and n is 1.

Preferably, in Formula (II), n is 1.

Preferably, in Formula (II), n is 2.

Preferably, q is 1.

Preferably, —N(R^(a))R^(b) is amino, methylamino, ethylamino,isopropylamino, dimethylamino, diethylamino, diisopropylamino,cyclopropylamino, cyclopentylamino, piperidinyl, pyrrolidinyl,morpholinyl, thiomorpholinyl, or piperazinyl.

More preferably, —N(R^(a))R^(b) is amino, methylamino, dimethylamino, orN-methylpiperazinyl.

Preferably, A is >NR¹.

Preferably, R¹ is selected from the group consisting of hydrogen,methyl, ethyl, isopropyl, butyl, hexyl, cyclopropyl, cyclobutyl,cyclopentyl, and benzyl, each optionally mono-, di-, or tri-substitutedwith R^(e).

More preferably, R¹, optionally R^(e) substituted, is selected from thegroup consisting of hydrogen, methyl, ethyl, isopropyl, and benzyl.

Even more preferably, R¹ is hydrogen or methyl.

Preferably, R³, optionally substituted, is selected from the groupconsisting of methyl, ethyl, propyl, isopropyl, butyl, methylene, allyl,and benzyl. Alternatively, two R³ substituents taken together formethylene.

More preferably, R³ is methyl.

Preferably, r is 0, 1, or 2.

Preferably Ar, optionally substituted, is selected from the groupconsisting of:

a) phenyl, 5-,6-,7-,8-benzo-1,4-dioxanyl, 4-,5-,6-,7-benzo-1,3-dioxolyl,4-,5-,6-,7-indolinyl, 4-,5-,6-,7-isoindolinyl,1,2,3,4-tetrahydro-quinolin-4,5,6 or 7-yl,1,2,3,4-tetrahydro-isoquinolin-4,5,6 or 7-yl,

b) furanyl, oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl,1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, thiophenyl, thiazolyl,isothiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl,1,2,4-triazolyl,

c) pyridinyl, pyridinyl-N-oxide, pyrazinyl, pyrimidinyl, pyridazinyl,and

d) biphenyl, and 4-tetrazolylphenyl.

More preferably, Ar, optionally substituted, is selected from the groupconsisting of phenyl, pyridyl, thiophen-2-yl, and thiophen-3-yl.

Specific Ar may be selected from the group consisting of phenyl,2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-methylphenyl,3-methylphenyl, 4-methylphenyl, 4-ethylphenyl, 2-chlorophenyl,3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl,4-fluorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl,2-trifluoromethylphenyl, 3-trifluoromethylphenyl,4-trifluoromethylphenyl, 3-trifluoromethoxyphenyl,4-trifluoromethoxyphenyl, 3-cyanophenyl, 4-cyanophenyl, 3-acetylphenyl,4-acetylphenyl, 3,4-difluorophenyl, 3,4-dichlorophenyl,2,3-difluorophenyl, 2,3-dichlorophenyl, 2,4-difluorophenyl,2,4-dichlorophenyl, 3-nitrophenyl, 4-nitrophenyl,3-chloro-4-fluorophenyl, 3-fluoro-4-chlorophenyl, benzo[1,3]dioxol-4 or5-yl, 3-hydroxyphenyl, 4-hydroxyphenyl, 4-hydroxy-2-methylphenyl,4-hydroxy-3-fluorophenyl, 3,4-dihydroxyphenyl,4-dimethylaminophenyl,4-carbamoylphenyl, 4-fluoro-3-methylphenyl, 2-phenoxyphenyl, furan-2-yl,furan-3-yl, 5-methyl-furan-2-yl, thiophen-2-yl, thiophen-3-yl,5-chlorothiophen-2-yl, 5-methylthiophen-2-yl, 5-chlorothiophen-3-yl,5-methylthiophen-3-yl, oxazol-2-yl, 4,5-dimethyl-oxazol-2-yl,thiazol-2-yl, 3H-[1,2,3]triazol-4-yl, 2H-pyrazol-3-yl, 1H-pyrazol-4-yl,4-pyridyl, 5-fluoro-pyridin-2-yl, 4′-chlorobiphenyl, and4-tetrazolylphenyl.

Preferably, ALK, optionally substituted, is selected from the groupconsisting of methylene, ethylene, propylene, butylene, sec-butylene,tert-butylene, pentylene, 1-ethylpropylene, 2-ethylpropylene,2-ethylbutylene, isopropylene, but-3-enylene, isobutylene,3-methylbutylene, allylene, prop-2-ynylene, cyclopropylene,cyclobutylene, cyclopentylene, cyclohexylene, and cycloheptylene.

Specific ALK may be selected from the group consisting of methylene,hydroxymethylene, fluoromethylene, difluoromethylene,trifluoromethylmethylene, 2,2,2-trifluoro-1-trifluoromethyl-ethylene,methoxycarbonylmethyl, methylcarbamoylmethyl, ethylene,2-dimethylaminoethylene, 2-cyanoethylene, 2-methoxyethylene,1-carboxy-ethylene, propylene, 3-methoxycarbonyl propylene, 3-carboxypropylene, isopropylene, 1-fluoro-1-methyl-ethylene,1-hydroxy-1-methyl-ethylene, 1-carboxy-1-methyl-ethylene,1-ethylpropylene, 2-ethylpropylene, butylene, tert-butylene,sec-butylene, isobutylene, 4-hydroxybutylene, 4-methoxycarbonylbutylene, 4-carboxy butylene, 2-ethylbutylene, isobutylene,3-methylbutylene, prop-2-ynylene, but-3-enylene, pentylene,5-hydroxypentylene, cyclopropylene, cyclobutylene, cyclopentylene,cyclopentenylene, 3,3-difluoro-cyclopentylene, 3-hydroxy-cyclohexylene,4-fluorocyclohexylene, 4,4-difluoro-cyclohexylene, and1-methyl-cyclopropylene.

Preferably CYC, optionally substituted, is hydrogen or is a ring systemselected from the group consisting of:

i) phenyl, 5-,6-,7-,8-benzo-1,4-dioxanyl, 4-,5-,6-,7-benzo-1,3-dioxolyl,4-,5-,6-,7-indolinyl, 4-,5-,6-,7-isoindolinyl,1,2,3,4-tetrahydro-quinolin-4,5,6 or 7-yl,1,2,3,4-tetrahydro-isoquinolin-4,5,6 or 7-yl,

ii) furanyl, oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl,1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, thiophenyl, thiazolyl,isothiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl,1,2,4-triazolyl,

iii) pyridinyl, pyridinyl-N-oxide, pyrazinyl, pyrimidinyl, pyridazinyl,and

iv) pyrrolinyl, pyrrolidinyl, pyrazolinyl, piperidinyl, homopiperidinyl,azepanyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl,morpholinyl, thiomorpholinyl, and piperidinonyl.

More preferably, CYC, optionally substituted, is selected from the groupconsisting of hydrogen, phenyl, thiophen-2-yl, thiophen-3-yl,furan-2-yl, furan-3-yl, pyridinyl, piperidin-1,2,3 or 4-yl,2-pyrrolin-2,3,4, or 5-yl, 3-pyrrolin-2 or 3-yl, 2-pyrazolin-3,4 or5-yl, tetrahydrofuran-3-yl, tetrahydropyran-4-yl, morpholin-2,3, or4-yl, thiomorpholin-2,3, or 4-yl, piperazin-1,2,3, or 4-yl,pyrrolidin-1,2, or 3-yl, and homopiperidinyl.

Most preferably, CYC, optionally substituted, is selected from the groupconsisting of hydrogen, phenyl, pyridyl, thiophen-2-yl, thiophen-3-yl,tetrahydropyranyl, furan-2-yl, furan-3-yl, tetrahydrofuran-3-yl, andpiperidinyl.

Specific CYC may be selected from the group consisting of hydrogen,phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl,2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 4-ethylphenyl,2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl,3-fluorophenyl, 4-fluorophenyl, 2-bromophenyl, 3-bromophenyl,4-bromophenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl,4-trifluoromethylphenyl, 3-trifluoromethoxyphenyl,4-trifluoromethoxyphenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl,3-acetylphenyl, 4-acetylphenyl, 3,4-difluorophenyl, 3,4-dichlorophenyl,2,3-difluorophenyl, 2,3-dichlorophenyl, 2,4-difluorophenyl,2,4-dichlorophenyl, 2,6-difluorophenyl, 2,6-dichlorophenyl,2,6-dimethylphenyl, 2,4,6-trifluorophenyl, 2,4,6-trichlorophenyl,3,4,5-trimethoxyphenyl, 4-fluoro-3-methylphenyl, 3-nitrophenyl,4-nitrophenyl, 4-methyl-3-fluorophenyl, 3,4-dimethylphenyl,4-methoxy-3-fluorophenyl, 4-methoxy-2-methylphenyl, 3-aminophenyl,4-aminophenyl, 4-carbomethoxyphenyl, 3-methanesulfonylamino-phenyl,4-methanesulfonylamino-phenyl, 3-dimethanesulfonylamino-phenyl,4-dimethanesulfonylamino-phenyl, thiophen-2-yl, thiophen-3-yl,5-chlorothiophen-2-yl, benzo[1,3]dioxol-4 or 5-yl, tetrahydrofuran-3-yl,tetrahydropyran-2,3 or 4-yl, furan-2-yl, furan-3-yl,5-carboxyethyl-furan-2-yl, piperidinyl, 3,4-bisbenzyloxyphenyl,2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl,4-hydroxy-2-methylphenyl, 4-hydroxy-3-fluorophenyl, 3,4-dihydroxyphenyl,1-piperidinyl, 4-piperidinyl, and 1-methyl-4-piperidinyl.

In one embodiment of Formula (I), CYC-(ALK)_(q)— is —C₃₋₈cycloalkyl.

In another embodiment of Formula (I), CYC-(ALK)_(q)— is not methyl,ethyl, propyl, or isopropyl where A is >NR¹. In another embodiment ofFormula (I), CYC-(ALK)_(q)— is not methyl, ethyl, propyl, or isopropyl.In another embodiment of Formula (I), m is not 2. In another embodimentof Formula (I), A is not unsubstituted —CH₂— where q is 0.

Compounds of Formulae (I) and (II) comprise compounds that satisfy anyone of the combinations of definitions given herein and equivalentsthereof.

It is understood that the symbol “>” when used herein immediately priorto an atom means that the atom immediately following this symbol isdivalent.

It is understood that some compounds referred to herein are chiraland/or have geometric isomeric centers, for example E- and Z-isomers.The present invention encompasses all such optical isomers, includingdiastereomers and racemic mixtures, atropisomers, and geometric isomers,and mixtures thereof, that possess the activity that characterizes thecompounds of this invention. In addition, certain compounds referred toherein can exist in solvated as well as unsolvated forms. It isunderstood that this invention encompasses all such solvated andunsolvated forms that possess the activity that characterizes thecompounds of this invention.

Compounds according to the present invention that have been modified tobe detectable by some analytic technique are also within the scope ofthis invention. The compounds of the present invention may be labeledwith radioactive elements such as ¹²⁵I, ¹⁸F, ¹¹C, ⁶⁴Cu, ³H, ¹⁴C, and thelike for use in imaging or for radioactive treatment of patients. Anexample of such compounds is an isotopically labeled compound, such asan ¹⁸F isotopically labeled compound that may be used as a probe indetection and/or imaging techniques, such as positron emissiontomography (PET) and single-photon emission computed tomography (SPECT).Preferably, compounds of the present invention labeled with ¹⁸F or ¹¹Cmay be used as a positron emission tomography (PET) molecular probe forstudying serotonin-mediated disorders. Alternatively, compounds of thepresent invention labeled with ¹⁴C may be used in metabolic studies.Another example of such compounds is an isotopically labeled compound,such as a deuterium and/or tritium labeled compound, that may be used inreaction kinetic studies. The compounds described herein may be reactedwith an appropriate functionalized radioactive reagent usingconventional chemistry to provide radiolabeled compounds.

Preferred compounds, which are pyrimidines, are selected from the groupconsisting of:

Ex. Chemical Name 12-tert-Butyl-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;22-Benzyl-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;32-sec-Butyl-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidinehydrochloride; 42-sec-Butyl-4-p-tolyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidinehydrochloride; 52-Cyclobutyl-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidinehydrochloride; 62-Cyclobutyl-4-p-tolyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine; 72-Cyclopropyl-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine; 82-Benzyl-4-p-tolyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine; 92-Benzyl-4-(4-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine; 102-Benzyl-4-(3,4-difluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;11 2-Benzyl-4-phenyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine; 122-Benzyl-4-(3-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;132-(4-Fluoro-benzyl)-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine; 142-(4-Fluoro-benzyl)-4-(4-fluoro-phenyl)-6-methyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine; 154-[2-(4-Fluoro-benzyl)-6-methyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yl]-benzonitrile; 164-[2-(4-Fluoro-benzyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yl]-benzonitrile; 172-Cyclopentyl-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;18 2-Cyclopentyl-4-p-tolyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;19 2-Cyclopentyl-4-(4-methoxy-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine; 204-(2-Cyclopentyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yl)-benzonitrile;214-(4-Fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidinehydrochloride; 224-(4-Fluoro-phenyl)-2-isopropyl-6-methyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine; 234-(3,4-Dichloro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine hydrochloride; 244-(3,4-Difluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine hydrochloride; 254-(3-Fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;264-(2-Fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;27 4-(2,4-Difluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine; 282-Isopropyl-4-p-tolyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine; 294-(4-Chloro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;30 2-Isopropyl-4-(4-methoxy-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine; 312-Isopropyl-4-phenyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine; 322-Isopropyl-4-(4-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine; 332-Isopropyl-4-(2-phenoxy-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine; 342-Isobutyl-4-thiophen-3-yl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;352-Isobutyl-4-thiophen-2-yl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;36 2-Isobutyl-4-pyridin-4-yl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;374-(4-Fluoro-phenyl)-2-isobutyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;38 2-Isobutyl-4-p-tolyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine; 394-(4-Fluoro-3-methyl-phenyl)-2-isobutyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine; 404-(2-Isobutyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yl)-benzonitrile;412-Isobutyl-4-(4-methoxy-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;422-sec-Butyl-4-(2-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidinehydrochloride; 432-sec-Butyl-4-(3-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;44 2-sec-Butyl-4-(4-methoxy-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine; 452-sec-Butyl-4-(4-trifluoromethoxy-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine; 462-Cyclopentyl-4-(4-fluoro-phenyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine; 472-Cyclopentyl-4-p-tolyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine; 482-Cyclopentyl-4-(4-methoxy-phenyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine; 494-(2-Cyclopentyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl)-benzonitrile; 504-(4-Fluoro-phenyl)-2-isopropyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine hydrochloride; 514-(4-Chloro-phenyl)-2-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine;52 2-Methyl-4-phenyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine; 534-(3-Chloro-phenyl)-2-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine;542-Benzyl-4-(4-fluoro-phenyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine;55 2-Benzyl-4-p-tolyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine; 562-Benzyl-4-(4-trifluoromethyl-phenyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine; 572-(4-Fluoro-benzyl)-4-(4-fluoro-phenyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine; 582-Cyclopentyl-4-(4-fluoro-phenyl)-7-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine; 592-Cyclopentyl-7-methyl-4-p-tolyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine; 602-Cyclopentyl-4-(4-methoxy-phenyl)-7-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine; 612-Benzyl-7-methyl-4-p-tolyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine;622-(4-Fluoro-benzyl)-4-(4-fluoro-phenyl)-7-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine; 632-(4-Fluoro-benzyl)-4-(4-fluoro-phenyl)-7-methyl-9-methylene-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine; 642-Benzyl-4-(4-fluoro-phenyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepinehydrochloride; 654-(4-Fluoro-phenyl)-2-isopropyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepine hydrochloride; 662-Isopropyl-4-p-tolyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepinehydrochloride; 672-Isopropyl-4-(4-methoxy-phenyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepine; 682-Isopropyl-4-phenyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepine; 692-Benzyl-4-(4-fluoro-phenyl)-6,7,8,9-tetrahydro-5H-1,3,6-triaza-benzocycloheptene hydrochloride; 702,7-Dibenzyl-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidinehydrochloride; 712,7-Dibenzyl-4-p-tolyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine; 722,7-Dibenzyl-4-phenyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine; 732,7-Dibenzyl-4-(4-methoxy-phenyl)-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine; 747-Benzyl-4-(4-fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine; 757-Benzyl-2-isopropyl-4-phenyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine;762-Benzyl-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidinehydrochloride; 772-Benzyl-4-p-tolyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidinehydrochloride; 782-Benzyl-4-phenyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine; 792-Benzyl-4-(4-methoxy-phenyl)-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine;804-(4-Fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidinehydrochloride; 812-Isopropyl-4-phenyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine; 822-Benzyl-4-(4-fluoro-phenyl)-7-methyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine hydrochloride; 832-Benzyl-4-(4-fluoro-phenyl)-7-isopropyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine; 844-(4-Fluoro-phenyl)-2-isopropyl-7-methyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine hydrochloride; 852-Isopropyl-7-methyl-4-phenyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine;86 7-Benzyl-2-isopropyl-4-(5-methyl-thiophen-3-yl)-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine hydrochloride; 877-Benzyl-2-isopropyl-4-thiophen-3-yl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine hydrochloride; 882-Isopropyl-4-(5-methyl-thiophen-3-yl)-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine hydrochloride; 892-Isopropyl-4-thiophen-3-yl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidinehydrochloride; 902-Isopropyl-7-methyl-4-(5-methyl-thiophen-3-yl)-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine hydrochloride; 912-Isopropyl-7-methyl-4-thiophen-3-yl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine hydrochloride; 926-Benzyl-4-(4-fluoro-phenyl)-2-isopropyl-8-methyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine; 936-Benzyl-4-(3-chloro-4-fluoro-phenyl)-2-isopropyl-8-methyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine; 946-Benzyl-2-isopropyl-8-methyl-4-p-tolyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine; 956-Benzyl-2-isopropyl-8-methyl-4-phenyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine; 966-Benzyl-2-isopropyl-8-methyl-4-(4-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine; 976-Benzyl-4-(4-chloro-phenyl)-2-isopropyl-8-methyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine; 986-Benzyl-2-isopropyl-8-methyl-4-thiophen-3-yl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine; 996-Benzyl-4-(4′-chloro-biphenyl-4-yl)-2-isopropyl-8-methyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine; 1004-(4-Fluoro-phenyl)-2-isopropyl-8-methyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine hydrochloride; 1014-(3-Chloro-4-fluoro-phenyl)-2-isopropyl-8-methyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine hydrochloride; 1022-Isopropyl-8-methyl-4-p-tolyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidinehydrochloride; 1032-Isopropyl-8-methyl-4-phenyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;1042-Isopropyl-8-methyl-4-(4-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine; 1052-Isopropyl-8-methyl-4-thiophen-3-yl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine; 1064-(4-Fluoro-phenyl)-2-isopropyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidinehydrochloride; 1074-(4-Fluoro-phenyl)-2-isopropyl-7-pyrrolidin-1-yl-5,6,7,8-tetrahydro-quinazoline; 108[4-(4-Fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-quinazolin-7-yl]-methyl-amine hydrochloride; 109[4-(4-Fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-quinazolin-6-yl]-methyl-amine hydrochloride; 1104-(4-Fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-quinazolin-7-ol; 1114-(4-Fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-quinazoline; 112(2-Benzyl-6-p-tolyl-pyrimidin-4-ylmethyl)-dimethyl-amine; 1132-Benzyl-4-(4-methyl-piperazin-1-ylmethyl)-6-p-tolyl-pyrimidine; 114[6-(4-Fluoro-phenyl)-2-isopropyl-pyrimidin-4-ylmethyl]-methyl-amine; 1152-(2-Benzyl-6-p-tolyl-pyrimidin-4-yl)-ethylamine; 116[2-(4-Fluoro-benzyl)-4-p-tolyl-pyrimidin-5-ylmethyl]-dimethyl-amine; 1174-(4-Fluoro-phenyl)-2-phenyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;118 2-(3,3-Difluoro-cyclopentyl)-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine; 1194-(4-Fluoro-phenyl)-2-(tetrahydro-furan-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine; 1204-(4-Fluoro-phenyl)-2-(2-piperidin-1-yl-ethyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine; 1212-(1-Fluoro-1-methyl-ethyl)-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine; 1223-(4-Fluoro-phenyl)-5-isopropyl-4,6,12-triaza-tricyclo[7.2.1.0^(2,7)]dodeca-2,4,6-triene; 1237-(4-Fluoro-phenyl)-5-isopropyl-4,6,13-triaza-tricyclo[8.2.1.0^(3,8)]trideca-3,5,7-triene; 1244-(4-Fluoro-phenyl)-2-(tetrahydro-pyran-4-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine; 1254-(4-Fluoro-phenyl)-2-(tetrahydro-pyran-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine; 1264-(4-Fluoro-phenyl)-2-(2-methoxy-ethyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine; 1272-[4-(4-Fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl]-propan-2-ol; 1284-(4-Fluoro-phenyl)-2-(1-methyl-1-phenyl-ethyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine; 1292-Cyclopent-3-enyl-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine; 1303-[4-(4-Fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl]-cyclohexanol; 1314-(4-Fluoro-phenyl)-2-piperidin-4-yl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine; 1324-(4-Fluoro-phenyl)-2-(1-methyl-piperidin-4-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine; 133[4-(4-Fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl]-phenyl-methanol; 1344-(4-Fluoro-phenyl)-2-(fluoro-phenyl-methyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine; 1352-(Difluoro-phenyl-methyl)-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine; 1364-(4-Fluoro-phenyl)-2-phenyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;1374-(4-Fluoro-phenyl)-2-(3-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine; 1384-(4-Fluoro-phenyl)-2-(4-methoxy-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine; 1394-(4-Fluoro-phenyl)-2-o-tolyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;1403-[4-(4-Fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl]-benzonitrile; 1414-(4-Fluoro-phenyl)-2-(2,2,2-trifluoro-1-trifluoromethyl-ethyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine; 1424-(4-Fluoro-phenyl)-2-(1-methyl-cyclopropyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine; 1432-[4-(4-Fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl]-2-methyl-propionic acid; 1442-[4-(4-Fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl]-propionic acid; 1452-(4-Fluoro-cyclohexyl)-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine; 1462-(4,4-Difluoro-cyclohexyl)-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine; 1474-(4-Fluoro-phenyl)-2-phenethyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;148 4-Furan-2-yl-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;149 2-Isopropyl-4-(5-methyl-furan-2-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine; 1504-Furan-3-yl-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine; 1514-(5-Fluoro-pyridin-2-yl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine; 1522-Isopropyl-4-oxazol-2-yl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;1534-(4,5-Dimethyl-oxazol-2-yl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine; 1542-Isopropyl-4-thiazol-2-yl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;1552-Isopropyl-4-(3H-[1,2,3]triazol-4-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine; 1562-Isopropyl-4-(2H-pyrazol-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;1572-Isopropyl-4-(1H-pyrazol-4-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;158 4-(4-Fluoro-phenyl)-2,6-diisopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine; 1596-Ethyl-4-(4-fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine; 1606-Cyclopropyl-4-(4-fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine; 1616-Cyclobutyl-4-(4-fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine; 1626-Cyclopentyl-4-(4-fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine; 1636-Butyl-4-(4-fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine; 1654-(4-Fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine,citrate salt; 166{2-[2-tert-Butyl-6-(4-fluoro-phenyl)-pyrimidin-4-yl]-ethyl}-methyl-amine;and 167{2-[2-tert-Butyl-6-(4-fluoro-phenyl)-pyrimidin-4-yl]-ethyl}-dimethyl-amine.

Preferably, the compound is4-(4-fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidineor a pharmaceutically acceptable salt thereof.

The features and advantages of the invention are apparent to one ofordinary skill in the art. Based on this disclosure, including thesummary, detailed description, background, examples, and claims, one ofordinary skill in the art will be able to make modifications andadaptations to various conditions and usages. Publications describedherein are incorporated by reference in their entirety. Where chemicalsymbols are used, it is understood that they are read from left toright, and that otherwise their spatial orientation has no significance.

The compounds as described above may be made according to processeswithin the skill of the art and/or that are described in the schemes andexamples that follow. To obtain the various compounds herein, startingmaterials may be employed that carry the ultimately desired substituentsthough the reaction scheme with or without protection as appropriate.This may be achieved by means of conventional protecting groups, such asthose described in “Protective Groups in Organic Chemistry”, ed. J. F.W. McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts,“Protective Groups in Organic Synthesis”, 3^(rd) ed., John Wiley & Sons,1999. The protecting groups may be removed at a convenient subsequentstage using methods known from the art. Alternatively, it may benecessary to employ, in the place of the ultimately desired substituent,a suitable group that may be carried through the reaction scheme andreplaced as appropriate with the desired substituent. Such compounds,precursors, or prodrugs are also within the scope of the invention.Reactions may be performed between the melting point and the refluxtemperature of the solvent, and preferably between 0° C. and the refluxtemperature of the solvent.

The pyrimidine compounds of Formulae (I) and (II) may be prepared by anumber of reaction schemes. Access to compounds of Formulae (I) and (II)is described in Schemes 1-5. Persons skilled in the art will recognizethat certain compounds are more advantageously produced by one scheme ascompared to the other. In addition to the Schemes shown below,alternative methods may be used to prepare compounds of Formulae (I) or(II). Such methods are described in U.S. patent application Ser. No.10/941,664 (Carruthers et al.), which is hereby incorporated byreference.

Table of Acronyms Term Acronym Tetrahydrofuran THF N,N-DimethylformamideDMF N,N-Dimethylacetamide DMA Dimethyl sulfoxide DMSOtert-Butylcarbamoyl Boc High-pressure liquid chromatography HPLC Thinlayer chromatography TLC N,N-Diisopropylethylamine DIEA1,2-Dichloroethane DCE Ethylene glycol dimethyl ether DME Acetyl AcDiisobutylaluminum hydride DIBAL-H Ethyl acetate EtOAc Trifluoroaceticacid TFA Methanesulfonyl chloride MsCl

Referring to Scheme 1, compounds of Formula (I) may be prepared frombeta-ketoesters (V), where G may be A or a protected form of A. Where Acontains an amine group, the amine moiety may be suitably protected asan alkyl or benzyl amine, amide, carbamate, or other suitable group.Preferred protecting groups for amines include the t-butyl carbamate(Boc) or benzyl groups. Beta-ketoesters (V) are available according tomethods known to one skilled in the art. Compounds of formula (V) arereacted with amidines (VI), prepared, for example, in the presence ofKOtBu or a tertiary amine base such as Et₃N, in a solvent such as tBuOH,at temperatures ranging from room temperature to the reflux temperatureof the solvent, to form hydroxy pyrimidines (VII). (See also: U.S.Patent Appl. 60/326,662; Tetrahedron 1989, 45(20), 651 1). Pyrimidines(VII) can be converted into precursors for transition metal-catalyzedcross-coupling reactions, such as Stille, Suzuki, Negishi or other suchcoupling reactions known to one skilled in the art. For example,treatment with POCl₃, PCl₃, PCl₅, PBr₃ or POBr₃ can afford thecorresponding halopyrimidines, where Y is bromide or chloride.Preferably, pyrimidines (VII) are treated with a triflating agent suchas trifluoromethane-sulfonic anhydride orN-phenyl-bis(trifluoromethanesulfonimide) in DCE, CH₂Cl₂, THF, or thelike, in the presence of a base such as pyridine, Et₃N, DIEA, or KOtBu,to provide triflates of formula (VII) where Y is OTf. Coupling ofhalides or triflates (VIII) with aryl boronic acids (IX), or theirboronic ester analogs, in the presence of a catalyst such as Pd(PPh₃)₄,PdCl₂(PPh₃)₂, PdCl₂(Po-tol₃)₂, PdCl₂(dppe) or PdCl₂(dppf), in a solventsuch as THF, 1,4-dioxane, DMA, DMF, DME, toluene, toluene/ethanol, ortoluene/H₂O mixtures, in the presence of a base such as Na₂CO₃, K₂CO₃,Cs₂CO₃, K₃PO₄, KF, CsF, or KOAc, affords pyrimidines (X). Preferredcatalysts are Pd(PPh₃)₄ and PdCl₂(dppf), with or without additives suchas dppf and catalytic Bu₄NBr. Preferred conditions include PdCl₂(dppf),catalytic dppf, and K₃PO₄ in 1,4-dioxane.

Where G contains a protecting group, it may be removed using generallyaccepted methods, or may be otherwise converted into A of Formula (I).More specifically, a group such as a t-butyl carbamate may be removedwith an acid such as trifluoroacetic acid or HCl, in a solvent such asCH₂Cl₂, dioxane, EtOH, or MeOH to afford compounds of Formula (I). WhereG contains a benzyl group, said group may be removed according tostandard methods, including hydrogenation in the presence of a palladiumcatalyst such as Pd/C, in a solvent such as EtOH, or through reactionwith 1-chloroethylchloroformate in DCE.

Compounds of formula (X) where G is >NH may be further converted intoadditional embodiments of Formula (I) wherein A is >NR¹ usingconventional synthetic methods such as reductive amination or alkylationprotocols. Thus, treatment of amines (X) with a suitable aldehyde in thepresence of a reductant such as NaBH₄, NaBH₃CN, NaBH(OAc)₃, or H_(2(g)),in the presence of a catalyst, in a solvent such as CH₂Cl₂, DCE, THF,EtOH, or MeOH affords compounds of Formula (I) where A is >NR¹. Oneskilled in the art will recognize that the addition of an acid such asAcOH, Ti(O-iPr)₄, trifluoroacetic acid, or HCl, may be required.Alternatively, compounds (X) where G is >NH may be treated with analkylating agent, such as an alkyl chloride, bromide, iodide, mesylateor tosylate, in a solvent such as DMF, DMA, THF, or EtOH, and in thepresence of a base such as NaHCO₃, Na₂CO₃, K₂CO₃ or Cs₂CO₃ will producecompounds of Formula (I) where A is >NR¹.

In the following Schemes, the R³ substituents of Formula (I) andintermediates have been removed to simplify the structural depictions,but one skilled in the art will recognize that the procedures shownprovide access to compounds of Formula (I) containing the R³substituents.

Referring to Scheme 2, compounds of formula (X′), where PG is a ketoneprotecting group, may be prepared according to the methods described inScheme 1. Compounds (X′) may subsequently be converted into additionalembodiments of Formula (I), exemplified by compounds (XII), (XIII), and(XIV). Reductive amination of ketones (XI) may be accomplished asdescribed in Scheme 1. Alternatively, ketones (XI) may be reduced usingconventional methods such as NaBH₄ in EtOH or DIBAL-H in THF to thecorresponding secondary alcohols (XIV), or reduced completely viahydrogenation, Wolff-Kishner reduction, or other protocols to formcarbocycles (XIII).

Compounds of Formula (II) may be accessed according to Scheme 3. Alkynes(XV) where R is a suitable protected alcohol or amine are first coupledwith a suitable acid chloride (XVI), in the presence of a palladiumcatalyst such as Pd(PPh₃)₂Cl₂, a base such as Et₃N, an additive such asCuI, in a solvent such as THF to form intermediate alkynyl ketones. Saidketones are reacted in situ with amidines (VI), under conditions asdescribed in Scheme 1, to form pyrimidines (XVII). Alcohol and aminoprotecting groups may then be removed under standard conditions. Theresulting free amines are themselves compounds of Formula (II), but maybe further processed to additional embodiments of Formula (II) viareductive amination as described in Scheme 2. Where a free alcohol isliberated, said alcohol may be converted to —N(R^(a))R^(b) by: 1)formation of a suitable leaving group (an alkyl halide, mesylate, ortosylate); and 2) displacement with HN(R^(a))R^(b). Alternatively, theleaving group may be displaced by treatment with sodium azide.Subsequent reduction of the azido group under Staudinger conditionsgives a free amine. In another embodiment, the free alcohol may beoxidized to the corresponding aldehyde using, for example, Dess-Martinperiodinane or Swern oxidation conditions, and the resulting aldehydeconverted to —N(R^(a))R^(b) using reductive amination methods asdescribed in Scheme 1.

Alternatively, compounds of Formula (II) may be prepared according toScheme 4. Acrylate esters (XVIII) may be condensed with amidines (VI) asdescribed in Scheme 1 to form pyrimidines (XIX). The pendant ester groupmay be transformed into amines where n=1 by reduction to the alcohol,and either: 1) oxidizing to the corresponding aldehyde, and performing areductive amination to install the —N(R^(a))R^(b) substituent; or 2)activating the alcohol as a leaving group such as a tosylate, bromide,or chloride, and displacing with a suitable HN(R^(a))R^(b) reagent. Forn=2, the ester may be converted to an amide through peptide couplingmethods, and the amide reduced to the corresponding amine. For n=3,homologation procedures known to one skilled in the art may be used toinstall two carbon units.

Compounds of Formula (I) where A is >NH, and m and n are as defined inFormula (I), may be prepared according to Scheme 5. Ketones (XX) arecommercially available or may be prepared using methods known to oneskilled in the art. The nitrogen protecting group may be an acyl groupor carbamoyl group (such as a Boc group). Preferably, the nitrogenprotecting group is acetyl. Conversion to enamines of formula (XXI) isperformed by reaction with a secondary amine under standard waterremoval conditions. Preferably, the reaction is done with piperidine asthe secondary amine, and using a Dean Stark trap, with a catalyst suchas p-toluenesulfonic acid, in a solvent such as toluene. Elevatedtemperatures are preferred. Enamines are transformed into 1,3-diketones(XXII) by reaction with acyl chlorides (XVI), in the presence of asuitable base such as Et₃N, in a solvent such as CH₂Cl₂. See also:Breitenbucher, et al. PCT Intl. Appl. WO02/014314. Condensation withamidines of formula (VI) to form pyrimidines (XXIII) may be accomplishedas described in Scheme 1. Preferably, condensations are accomplished inthe presence of Et₃N, in a solvent such as t-amyl alcohol, attemperatures between room temperature and reflux temperature of thesolvent. Deprotection of the nitrogen protecting group may be effectedusing conditions known to one skilled in the art. Preferably, where theprotecting group is acetyl, deprotection is done in the presence of 10%aqueous HCl at reflux temperature. One skilled in the art will recognizethat compounds of Formula (I) prepared in Scheme 5 may be subsequentlyconverted to other embodiments where A is >NR¹ as described in Scheme 1.

Compounds of Formulae (I) or (II) may be converted to theircorresponding salts using methods known to those skilled in the art. Forexample, amines of Formulae (I) or (II) may be treated withtrifluoroacetic acid, HCl, or citric acid in a solvent such as MeOH toprovide the corresponding salt forms.

Compounds prepared according to the schemes described above may beobtained as single enantiomers, diastereomers, or regioisomers, or asracemic mixtures or mixtures of enantiomers, diastereomers, orregioisomers. Where regioisomeric or diastereomeric mixtures areobtained, isomers may be separated using conventional methods such aschromatography or crystallization. Where racemic (1:1) and non-racemic(not 1:1) mixtures of enantiomers are obtained, single enantiomers maybe isolated using conventional separation methods known to one skilledin the art. Particularly useful separation methods may include chiralchromatography, recrystallization, resolution, diastereomeric saltformation, or derivatization into diastereomeric adducts followed byseparation.

The present invention includes within its scope prodrugs of thecompounds of this invention. In general, such prodrugs will befunctional derivatives of the compounds that are readily convertible invivo into the required compound. Thus, in the methods of treatment ofthe present invention, the term “administering” shall encompass thetreatment of the various disorders described with a compound of Formula(I) or (II) or with a compound that converts to a compound of Formula(I) or (II) in vivo after administration to the patient. Conventionalprocedures for the selection and preparation of suitable prodrugderivatives are described, for example, in “Design of Prodrugs”, ed. H.Bundgaard, Elsevier, 1985. In addition to salts, the invention providesthe esters, amides, and other protected or derivatized forms of thedescribed compounds.

For therapeutic use, salts of the compounds of the present invention arethose that are pharmaceutically acceptable. However, salts of acids andbases that are non-pharmaceutically acceptable may also find use, forexample, in the preparation or purification of a pharmaceuticallyacceptable compound. All salts, whether pharmaceutically acceptable ornot are included within the ambit of the present invention.

Pharmaceutically acceptable salts, esters, and amides of compoundsaccording to the present invention refer to those salt, ester, and amideforms of the compounds of the present invention which would be apparentto the pharmaceutical chemist, i.e., those that are non-toxic and thatwould favorably affect the pharmacokinetic properties of said compoundsof the present invention. Those compounds having favorablepharmacokinetic properties would be apparent to the pharmaceuticalchemist, i.e., those which are non-toxic and which possess suchpharmacokinetic properties to provide sufficient palatability,absorption, distribution, metabolism and excretion. Other factors, morepractical in nature, which are also important in the selection, are costof raw materials, ease of crystallization, yield, stability,hygroscopicity and flowability of the resulting bulk drug.

Examples of acids that may be used in the preparation ofpharmaceutically acceptable salts include the following: acetic acid,2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginicacid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoicacid, 4-acetamidobenzoic acid, boric acid, (+)-camphoric acid,camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, capric acid,caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid,cyclohexanesulfamic acid, dodecylsulfuric acid, ethane-1,2-disulfonicacid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid,fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid,D-gluconic acid, D-glucuronic acid, L-glutamic acid, α-oxo-glutaricacid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid,hydroiodic acid, (+)-L-lactic acid, (±)-DL-lactic acid, lactobionicacid, lauric acid, maleic acid, (−)-L-malic acid, malonic acid,(±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid,naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinicacid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid,pamoic acid, perchloric acid, phosphoric acid, L-pyroglutamic acid,saccharic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid,stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaricacid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid, andvaleric acid.

Compounds of the present invention containing acidic protons may beconverted into their therapeutically active non-toxic metal or amineaddition salt forms by treatment with appropriate organic and inorganicbases. Appropriate base salt forms comprise, for example, the ammoniumsalts; the alkali and earth alkaline metal salts (e.g. lithium, sodium,potassium, magnesium, calcium salts, which may be prepared by treatmentwith, for example, magnesium hydroxide, calcium hydroxide, potassiumhydroxide, zinc hydroxide, or sodium hydroxide); and amine salts madewith organic bases (e.g. primary, secondary and tertiary aliphatic andaromatic amines such as L-arginine, benethamine, benzathine, choline,deanol, diethanolamine, diethylamine, dimethylamine, dipropylamine,diisopropylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylamine,ethylenediamine, isopropylamine, N-methyl-glucamine, hydrabamine,1H-imidazole, L-lysine, morpholine, 4-(2-hydroxyethyl)-morpholine,methylamine, piperidine, piperazine, propylamine, pyrrolidine,1-(2-hydroxyethyl)-pyrrolidine, pyridine, quinuclidine, quinoline,isoquinoline, secondary amines, triethanolamine, trimethylamine,triethylamine, N-methyl-D-glucamine,2-amino-2-(hydroxymethyl)-1,3-propanediol, and tromethamine). See, e.g.,S. M. Berge, et al., “Pharmaceutical Salts”, J. Pharm. Sci., 1977,66:1-19, and Handbook of Pharmaceutical Salts, Propertions, Selection,and Use; Stahl, P. H., Wermuth, C. G., Eds.; Wiley-VCH and VHCA: Zurich,2002, which are incorporated herein by reference.

Pharmaceutically acceptable esters and amides are those that are withina reasonable benefit/risk ratio, pharmacologically effective andsuitable for contact with the tissues of patients without unduetoxicity, irritation, or allergic response. Representativepharmaceutically acceptable amides of the invention include thosederived from ammonia, primary C₁₋₆alkyl amines and secondarydi(C₁₋₆alkyl) amines. Secondary amines include 5- or 6-memberedheterocyclic or heteroaromatic ring moieties containing at least onenitrogen atom and optionally between 1 and 2 additional heteroatoms.Preferred amides are derived from ammonia, C₁₋₃alkyl primary amines, anddi(C₁₋₂alkyl)amines.

Representative pharmaceutically acceptable esters of the inventioninclude C₁₋₇alkyl, C₅₋₇cycloalkyl, phenyl, substituted phenyl, andphenylC₁₋₆alkyl-esters. Preferred esters include methyl esters.Furthermore, examples of suitable esters include such esters where oneor more carboxyl substituents is replaced withp-methoxybenzyloxy-carbonyl, 2,4,6-trimethylbenzyloxy-carbonyl,9-anthryloxycarbonyl, CH₃SCH₂COO—, tetrahydrofur-2-yloxycarbonyl,tetrahydropyran-2-yloxy-carbonyl, fur-2-yloxycarbonyl,benzoylmethoxy-carbonyl, p-nitrobenzyloxy-carbonyl,4-pyridylmethoxycarbonyl, 2,2,2-trichloro-ethoxycarbonyl,2,2,2-tribromoethoxycarbonyl, t-butyloxycarbonyl, t-amyloxy-carbonyl,diphenylmethoxycarbonyl, triphenylmethoxycarbonyl,adamantyloxy-carbonyl, 2-benzyloxyphenyloxycarbonyl,4-methylthiophenyloxycarbonyl, or tetrahydropyran-2-yloxycarbonyl.

The compounds of the present invention are serotonin receptormodulators, and as such, the compounds are useful in the treatment ofserotonin-mediated disease states. Particularly, the compounds may beused in methods for treating or preventing CNS disorders, such as sleepdisorders, depression/anxiety, generalized anxiety disorder,schizophrenia, bipolar disorders, cognitive disorders, mild cognitiveimpairment, Alzheimer's disease, Parkinson's disease, psychoticdisorders, phobic disorders, obsessive-compulsive disorder, mooddisorders, post-traumatic stress and other stress-related disorders,migraine, pain, eating disorders, obesity, sexual dysfunction, metabolicdisturbances, hormonal imbalance, hot flushes associated with menopause,alcohol abuse, drug abuse, addictive disorders including drug addictionand alcohol addiction, nausea, inflammation, centrally mediatedhypertension, sleep/wake disturbances, jetlag, and circadian rhythmabnormalities. The compounds may also be used in the treatment andprevention of hypotension, peripheral vascular disorders, cardiovascularshock, renal disorders, gastric motility, diarrhea, spastic colon,irritable bowel disorders, ischemias, septic shock, urinaryincontinence, and other disorders related to the gastrointestinal andvascular systems. In addition, compounds of the present invention may beused in methods for treating or preventing a range of ocular disordersincluding glaucoma, optic neuritis, diabetic retinopathy, retinal edema,and age-related macular degeneration.

The compounds of the present invention are 5-HT₇ modulators and many are5-HT₇ antagonists. As such, the compounds are useful in methods fortreating or preventing 5-HT₇-mediated disease states. Where thecompounds possess substantial 5-HT₇ antagonist activity, they may beparticularly useful in methods for treating or preventingdepression/anxiety, sleep/wake disturbances, jetlag, migraine, urinaryincontinence, gastric motility, and irritable bowel disorders.

Many of the compounds of the present invention are 5-HT₂ modulators andmany are 5-HT₂ antagonists. As such, the compounds are useful in methodsfor treating or preventing 5-HT₂-mediated diseases and conditions. Wherethe compounds possess substantial 5-HT₂ antagonist activity, they may beparticularly useful in methods for treating or preventingdepression/anxiety, generalized anxiety disorder, schizophrenia, bipolardisorders, psychotic disorders, obsessive-compulsive disorder, mooddisorders, post-traumatic stress disorders, sleep disturbances, sexualdysfunction, hot flushes associated with menopause, eating disorders,migraine, addictive disorders, and peripheral vascular disorders.

The compounds of the present invention are 5-HT₆ modulators and many are5-HT₆ antagonists. As such, the compounds are useful in methods fortreating or preventing 5-HT₆-mediated disease states. Where thecompounds possess substantial 5-HT₆ antagonist activity, they may beparticularly useful in methods for treating or preventing schizophrenia,cognitive disorders, mild cognitive impairment, Alzheimer's disease, andParkinson's disease.

Said methods of treating and preventing comprise the step ofadministering to a mammal suffering therefrom an effective amount of atleast one compound of the present invention.

The present invention also contemplates a method of treating orpreventing a serotonin-mediated disease or condition with a combinationtherapy, comprising administering at least one compound of the presentinvention in combination with one or more neuroactive agents. Suitableneuroactive agents include: selective serotonin reuptake inhibitors(SSRIs), anti-psychotics, norepinephrine reuptake inhibitors (NRIs),sedatives, monoamine oxidase inhibitors (MAOs), and tricyclicantidepressants (TCAs). In another embodiment, the present inventionincludes compositions comprising at least one compound of the presentinvention and one or more neuroactive agent.

Compounds of the present invention may be administered in pharmaceuticalcompositions to treat patients (humans and other mammals) with disordersmediated by the serotonin receptor. Thus, the invention featurespharmaceutical compositions containing at least one compound of thepresent invention and a pharmaceutically acceptable carrier. Acomposition of the invention may further include at least one othertherapeutic agent (for example, a combination formulation or combinationof differently formulated active agents for use in a combination therapymethod).

The present invention also features methods of using or preparing orformulating such pharmaceutical compositions. The pharmaceuticalcompositions can be prepared using conventional pharmaceuticalexcipients and compounding techniques known to those skilled in the artof preparing dosage forms. It is anticipated that the compounds of theinvention can be administered by oral, parenteral, rectal, topical, orocular routes, or by inhalation. Preparations may also be designed togive slow release of the active ingredient. The preparation may be inthe form of tablets, capsules, sachets, vials, powders, granules,lozenges, powders for reconstitution, liquid preparations, orsuppositories. Preferably, compounds may be administered by intravenousinfusion or topical administration, but more preferably by oraladministration.

For oral administration, the compounds of the invention can be providedin the form of tablets or capsules, or as a solution, emulsion, orsuspension. Tablets for oral use may include the active ingredient mixedwith pharmaceutically acceptable excipients such as inert diluents,disintegrating agents, binding agents, lubricating agents, sweeteningagents, flavoring agents, coloring agents and preservatives. Suitableinert fillers include sodium and calcium carbonate, sodium and calciumphosphate, lactose, starch, sugar, glucose, methyl cellulose, magnesiumstearate, mannitol, sorbitol, and the like; typical liquid oralexcipients include ethanol, glycerol, water and the like. Starch,polyvinyl-pyrrolidone, sodium starch glycolate, microcrystallinecellulose, and alginic acid are suitable disintegrating agents. Bindingagents may include starch and gelatin. The lubricating agent, ifpresent, will generally be magnesium stearate, stearic acid or talc. Ifdesired, the tablets may be coated with a material such as glycerylmonostearate or glyceryl distearate to delay absorption in thegastrointestinal tract, or may be coated with an enteric coating.Capsules for oral use include hard gelatin capsules in which the activeingredient is mixed with a solid, semi-solid, or liquid diluent, andsoft gelatin capsules wherein the active ingredient is mixed with water,an oil such as peanut oil or olive oil, liquid paraffin, a mixture ofmono and di-glycerides of short chain fatty acids, polyethylene glycol400, or propylene glycol.

Liquids for oral administration may be suspensions, solutions, emulsionsor syrups or may be presented as a dry product for reconstitution withwater or other suitable vehicles before use. Compositions of such liquidmay contain pharmaceutically-acceptable excipients such as suspendingagents (for example, sorbitol, methyl cellulose, sodium alginate,gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminiumstearate gel and the like); non-aqueous vehicles, which include oils(for example, almond oil or fractionated coconut oil), propylene glycol,ethyl alcohol or water; preservatives (for example, methyl or propylp-hydroxybenzoate or sorbic acid); wetting agents such as lecithin; and,if needed, flavoring or coloring agents.

The compounds of this invention may also be administered by non-oralroutes. The compositions may be formulated for rectal administration asa suppository. For parenteral use, including intravenous, intramuscular,intraperitoneal, or subcutaneous routes, the compounds of the inventionwill generally be provided in sterile aqueous solutions or suspensions,buffered to an appropriate pH and isotonicity or in parenterallyacceptable oil. Suitable aqueous vehicles include Ringer's solution andisotonic sodium chloride. Such forms will be presented in unit dose formsuch as ampules or disposable injection devices, in multi-dose formssuch as vials from which the appropriate dose may be withdrawn, or in asolid form or pre-concentrate that can be used to prepare an injectableformulation. Another mode of administration of the compounds of theinvention may utilize a patch formulation to affect transdermaldelivery. The compounds of this invention may also be administered byinhalation, via the nasal or oral routes using a spray formulationconsisting of the compound of the invention and a suitable carrier.

Methods are known in the art for determining effective doses fortherapeutic (treatment) and prophylactic (preventative) purposes for thepharmaceutical compositions or the drug combinations of the presentinvention, whether or not formulated in the same composition. Thespecific dosage level required for any particular patient will depend ona number of factors, including severity of the condition being treated,the route of administration, and the weight of the patient. Fortherapeutic purposes, “effective dose” or “effective amount” refers tothat amount of each active compound or pharmaceutical agent, alone or incombination, that elicits the biological or medicinal response in atissue system, animal, or human that is being sought by a researcher,veterinarian, medical doctor, or other clinician, which includesalleviation of the symptoms of the disease or disorder being treated.For prophylactic purposes (i.e., preventing or inhibiting the onset orprogression of a disorder), the term “effective dose” or “effectiveamount” refers to that amount of each active compound or pharmaceuticalagent, alone or in combination, that inhibits in a subject the onset orprogression of a disorder as being sought by a researcher, veterinarian,medical doctor, or other clinician, the delaying of which disorder ismediated, at least in part, by the modulation of the serotonin receptor.Methods of combination therapy include co-administration of a singleformulation containing all active agents; essentially contemporaneousadministration of more than one formulation; and administration of twoor more active agents separately formulated.

It is anticipated that the daily dose (whether administered as a singledose or as divided doses) will be in the range 0.01 to 1000 mg per day,more usually from 1 to 500 mg per day, and most usually from 10 to 200mg per day. Expressed as dosage per unit body weight, a typical dosewill be expected to be between 0.0001 mg/kg and 15 mg/kg, especiallybetween 0.01 mg/kg and 7 mg/kg, and most especially between 0.15 mg/kgand 2.5 mg/kg.

Preferably, oral doses range from about 0.05 to 200 mg/kg, daily, takenin 1 to 4 separate doses. Some compounds of the invention may be orallydosed in the range of about 0.05 to about 50 mg/kg daily, others may bedosed at 0.05 to about 20 mg/kg daily, while still others may be dosedat 0.1 to about 10 mg/kg daily. Infusion doses can range from about 1 to1000 μg/kg/min of inhibitor, admixed with a pharmaceutical carrier overa period ranging from several minutes to several days. For topicaladministration compounds of the present invention may be mixed with apharmaceutical carrier at a concentration of about 0.1% to about 10% ofdrug to vehicle.

Examples

In order to illustrate the invention, the following examples areincluded. These examples do not limit the invention. They are only meantto suggest a method of practicing the invention. Those skilled in theart may find other methods of practicing the invention, which areobvious to them. However, those methods are deemed to be within thescope of this invention.

Preparative Reversed-Phase HPLC was performed as follows:

-   Method A. Instrument, Hewlett Packard Series 1100; Column, Agilent    ZORBAX® Bonus RP, 5 μm, 4.6×250 mm; Flow rate, 1 mL/min; Detection,    λ=220 & 254 nm; Gradient, 1 to 99% acetonitrile/water, 0.05%    trifluoroacetic acid over 20 min.-   Method B. Instrument, Hewlett Packard HPLC; Column, Agilent ZORBAX®    Eclipse XDB-C8, 5 μm, 4.6×150 mm; Flow rate, 1 mL/min; Detection,    λ=220 & 254 nm; Gradient, 1 to 99% acetonitrile/water, 0.05%    trifluoroacetic acid over 8 min.

Mass spectra were obtained on an Agilent series 1100 MSD usingelectrospray ionization (ESI) in either positive or negative modes asindicated.

Thin-layer chromatography was performed using Merck silica gel 60 F₂₅₄2.5 cm×7.5 cm 250 μm or 5.0 cm×10.0 cm 250 μm pre-coated silica gelplates. Preparative thin-layer chromatography was performed using EMScience silica gel 60 F₂₅₄ 20 cm×20 cm 0.5 mm pre-coated plates with a20 cm×4 cm concentrating zone.

NMR spectra were obtained on either a Bruker model DPX400 (400 MHz),DPX500 (500 MHz), or DPX600 (600 MHz) spectrometer. The format of the ¹HNMR data below is: chemical shift in ppm down field of thetetramethylsilane reference (multiplicity, coupling constant J in Hz,integration).

Example 12-tert-Butyl-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

Step A.2-tert-Butyl-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidinehydrochloride. To a tert-BuOH (17 mL) solution of4-oxo-piperidine-1,3-dicarboxylic acid-1-tert-butyl ester-3-ethyl ester(2.18 g, 8.05 mmol), and 2,2-dimethyl-propionamidine hydrochloride (1.0g, 7.3 mmol) was added Et₃N (3.0 mL, 22.0 mmol). The reaction solutionwas heated at reflux for 48 h, cooled to rt, and concentrated. Theresulting solid was dissolved in CH₂Cl₂ and washed with water. Theaqueous layer was extracted with CH₂Cl₂. The combined organic layerswere dried and concentrated to give a yellow solid that was trituratedwith Et₂O to give 1.74 g (70%) of the title compound as a white solid.MS (ESI): exact mass calcd. for C₁₆H₂₅N₃O₃, 307.19; m/z found, 308.4[M+H]⁺. ¹H NMR (CDCl₃): 4.35 (s, 2H), 3.68-3.67 (m, 2H), 2.74-2.65 (m,2H), 1.49 (s, 9H), 1.37 (s, 9H).

Step B.2-tert-Butyl-4-trifluoromethanesulfonyloxy-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carboxylicacid tert-butyl ester. To a 0° C. solution of the product from Step A(1.0 g, 3.25 mmol) in CH₂Cl₂ (16 mL) was added Et₃N (0.53 mL, 3.80 mmol)and trifluoromethanesulfonic anhydride (0.64 mL, 3.8 mmol) dropwise over10 min. After 2 h at 0° C., the mixture was diluted with CH₂Cl₂ andwashed with water. The aqueous layer was extracted with CH₂Cl₂. Thecombined organic layers were dried and concentrated. The resultingresidue was purified via SiO₂ chromatography (10-30% EtOAc/hexanes) togive 1.28 g (91%) of the title compound. MS (ESI): exact mass calcd. forC₁₇H₂₄F₃N₃O₃S, 439.14; m/z found, 440.3 [M+H]⁺. ¹H NMR (CDCl₃): 4.56 (s,2H), 3.77 (t, J=5.7, 2H), 2.99-2.95 (m, 2H), 1.50 (s, 9H), 1.36 (s, 9H).

Step C.2-tert-Butyl-4-(4-fluoro-phenyl)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carboxylicacid tert-butyl ester. To the product from Step B (0.17 g, 0.39 mmol)was added 4-fluorophenylboronic acid (0.082 g, 0.586 mmol), K₃PO₄ (0.124g, 0.584 mmol), Pd(Cl)₂dppf.CH₂Cl₂ (0.018 g, 0.022 mmol) and dppf (0.008g, 0.014 mmol). The mixture was evacuated with N₂, dioxane (4 mL) wasadded and the mixture was heated at reflux for 2 h. After cooling toroom temperature (rt), the mixture was diluted with Et₂O, filteredthrough a small SiO₂ plug, and the filtrate was concentrated. Theresulting residue was purified via SiO₂ chromatography (5-30%EtOAc/hexanes) to give 0.134 g (89%) of the title compound. MS (ESI):exact mass calcd. for C₂₂H₂₈FN₃O₂, 385.22; m/z found, 386.4 [M+H]⁺. ¹HNMR (CDCl₃): 7.60 (dd, J=5.4, 8.8, 2H), 7.17-7.14 (m, 2H), 4.59 (s, 2H),3.76 (t, J=6.1, 2H), 3.09 (t, J=6.1, 2H), 1.44 (s, 9H), 1.41 (s, 9H).

Step D.2-tert-Butyl-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidinehydrochloride. To an EtOAc solution of the product from Step D (0.130 g,0.337 mmol) was added 4 M HCl in dioxane. After stirring for 18 h thevolatiles were removed and the solid partitioned between water andEtOAc. The aqueous layer was made basic with 1 N NaOH and extracted withEtOAc (2×). The combined organic layers were dried with MgSO₄, filteredand concentrated. The resulting residue was purified via SiO₂chromatography (1-7% 2 M NH₃ in MeOH/CH₂Cl₂) to give 0.079 g (82%) ofthe title compound. The corresponding HCl salt was obtained upontreatment of the free base in Et₂O with 1 M HCl in Et₂O. MS (ESI): exactmass calcd. for C₁₇H₂₀FN₃, 285.16; m/z found, 286.4 [M+H]⁺. ¹H NMR(DMSO-d₆): 9.74 (s, 2H), 7.71 (dd, J=5.5, 8.6, 2H), 7.42 (d, J=8.8, 2H),4.31 (m, 2H), 3.49-3.48 (m, 2H), 3.16 (t, J=6.2, 2H), 1.38 (s, 9H).

Example 22-Benzyl-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine.

Step A.2-Benzyl-4-trifluoromethanesulfonyloxy-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carboxylicacid tert-butyl ester. To a solution of2-benzyl-4-hydroxy-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carboxylicacid tert-butyl ester (2.0 g, 5.9 mmol; prepared from2-phenyl-acetamidine hydrochloride as described in Example 1, Step A) inTHF (15 mL) was added KOtBu (0.408 g, 3.6 mmol). After 15 min, themixture was treated with N-phenyl-bis(trifluoromethanesulfonimide) (1.18g, 3.3 mmol) and the mixture was stirred for 18 h. The mixture wasdiluted with water and extracted with EtOAc (2×). The combined organiclayers were dried and concentrated. The resulting residue was purifiedvia SiO₂ chromatography (10-40% EtOAc/hexanes) to give 1.15 g (81%) ofthe title compound which was contaminated with byproducts fromN-phenyl-bis(trifluoromethanesulfonimide).

Step B.2-Benzyl-4-(4-fluoro-phenyl)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carboxylicacid tert-butyl ester. The title compound was prepared as described inExample 1, Step C. MS (ESI): exact mass calcd. for C₂₅H₂₆FN₃O₂, 419.20;m/z found, 420.5 [M+H]⁺. ¹H NMR (CDCl₃): 7.53 (dd, J=5.3, 8.7, 2H),7.43-7.41 (m, 2H), 7.31-7.28 (m, 2H), 7.23-7.14 (m, 3H), 4.55 (s, 2H),4.27 (s, 2H), 3.75 (t, J=6.1, 2H), 3.00 (t, J=6.0, 2H), 1.43 (s, 9H).

Step C.2-Benzyl-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine.A solution of the product from Step B (0.131 g, 0.312 mmol) in CH₂Cl₂was treated with TFA. After stirring for 4 h, the mixture wasconcentrated and partitioned between saturated (satd.) aq. NaHCO₃ andCH₂Cl₂ (2×). The combined organic layers were dried and concentrated.The resulting residue was purified via SiO₂ chromatography (1-7% 2 M NH₃in MeOH/CH₂Cl₂) to give 0.084 g (84%) of the title compound. MS (ESI):exact mass calcd. for C₂₀H₁₈FN₃, 319.15; m/z found, 320.4 [M+H]⁺. ¹H NMR(CDCl₃): 7.51 (dd, J=5.4, 8.8, 2H), 7.41 (d, J=7.4, 2H), 7.31-7.27 (m,2H), 7.22-7.19 (m, 1H), 7.15 (dd, J=8.7, 2H), 4.27 (s, 2H), 3.95 (s,2H), 3.24 (t, J=6.1, 2H), 2.97 (t, J=6.1, 2H).

Unless otherwise specified, the compounds in Examples 3-57 were preparedusing methods similar to those described in Examples 1 and 2, utilizingthe appropriate β-ketoesters, amidine hydrochlorides, and arylboronicacids.

Example 32-sec-Butyl-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidinehydrochloride

MS (ESI): exact mass calcd. for C₁₇H₂₀FN₃, 285.16; m/z found, 286.4[M+H]⁺. ¹H NMR (DMSO-d₆): 9.72 (s, 2H), 7.69 (dd, J=5.5, 8.8, 2H), 7.42(dd, J=8.8, 2H), 4.33-4.27 (m, 2H), 3.52-3.44 (m, 2H), 3.16 (t, J=6.4,2H), 2.96-2.88 (m, 1H), 1.88-1.77 (m, 1H), 1.66-1.56 (m, 1H), 1.26 (d,J=6.9, 3H), 0.83 (t, J=7.4, 3H).

Example 42-sec-Butyl-4-p-tolyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidinehydrochloride

MS (ESI): exact mass calcd. for C₂₁H₂₁N₃, 281.19; m/z found, 282.5[M+H]⁺. ¹H NMR (DMSO-d₆): 9.69 (s, 2H), 7.52 (d, J=8.1, 2H), 7.38 (d,J=7.4?, 2H), 4.33-4.26 (m, 2H), 3.52-3.54 (m, 2H), 3.15 (t, J=6.3, 2H),2.96-2.87 (m, 1H), 2.92 (m, 1H), 2.40 (s, 3H), 1.88-1.77 (m, 1H),1.67-1.55 (m, 1H), 1.26 (d, J=6.9, 3H), 0.83 (t, J=7.4, 3H).

Example 52-Cyclobutyl-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidinehydrochloride

MS (ESI): exact mass calcd. for C₁₇H₁₈FN₃, 283.15; m/z found, 284.3[M+H]⁺. ¹H NMR (DMSO-d₆): 9.72 (m, 2H), 7.70 (dd, J=5.5, 8.8, 2H),7.44-7.40 (m, 2H), 4.32-4.26 (m, 2H), 3.79-3.73 (m, 1H), 3.50-3.45 (m,2H), 3.16 (t, J=6.4, 2H), 2.42-2.27 (m, 4h), 2.08-1.99 (m, 1H),1.91-1.83 (m, 1H).

Example 62-Cyclobutyl-4-p-tolyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

Example 72-Cyclopropyl-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

MS (ESI): exact mass calcd. for C₁₆H₁₆FN₃, 269.13; m/z found, 270.3[M+H]⁺. ¹H NMR (DMSO-d₆): 9.81 (m, 2H), 7.67 (dd, J=5.4, 8.6, 2H), 7.40(dd, J=8.8, 2H), 4.26-4.22 (m, 2H), 3.48-3.42 (m, 2H), 3.11 (t, J=6.3,2H), 2.24-2.19 (m, 1H), 1.08-1.01 (m, 4H).

Example 8 2-Benzyl-4-p-tolyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

MS (ESI): exact mass calcd. for C₂₁H₂₁N₃, 315.17; m/z found, 316.4[M+H]⁺. ¹H NMR (CDCl₃): 7.43-7.41 (m, 4H), 7.30-7.25 (m, 4H), 7.21-7.18(m, 1H), 4.27 (s, 2H), 3.97 (s, 2H), 3.23 (t, J=6.1, 2H), 2.96 (t,J=6.1, 2H), 2.40 (s, 3H).

Example 92-Benzyl-4-(4-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

Example 102-Benzyl-4-(3,4-difluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

Example 11 2-Benzyl-4-phenyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

Example 122-Benzyl-4-(3-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

Example 132-(4-Fluoro-benzyl)-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

MS (ESI): exact mass calcd. for C₂₀H₁₇F₂N₃, 337.14; m/z found, 338.4[M+H]⁺. ¹H NMR (CDCl₃): 7.53-7.49 (m, 2H), 7.38-7.35 (m, 2H), 7.18-7.13(m, 2H), 6.99-6.95 (m, 2H), 4.23 (s, 2H), 3.96 (s, 2H), 3.25 (t, J=6.1,2H), 2.97 (t, J=6.1, 2H).

Example 142-(4-Fluoro-benzyl)-4-(4-fluoro-phenyl)-6-methyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

Example 154-[2-(4-Fluoro-benzyl)-6-methyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yl]-benzonitrile

Example 164-[2-(4-Fluoro-benzyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yl]-benzonitrile

Example 172-Cyclopentyl-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

MS (ESI): exact mass calcd. for C₁₈H₂₀FN₃, 297.16; m/z found, 298.4[M+H]⁺. ¹H NMR (CDCl₃): 7.55 (dd, J=5.4, 8.8, 2H), 7.15 (t, J=8.8, 2H),3.97 (s, 2H), 3.36-3.28 (m, 1H), 3.26 (t, J=6.1, 2H), 2.97 (t, J=6.1,2H), 2.12-1.64 (m, 8H).

Example 182-Cyclopentyl-4-p-tolyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

MS (ESI): exact mass calcd. for C₁₉H₂₃N₃, 293.19; m/z found, 294.5[M+H]⁺. ¹H NMR (CDCl₃): 7.55 (dd, J=5.4, 8.8, 2H), 7.15 (t, J=8.8, 2H),3.97 (s, 2H), 3.36-3.27 (m, 1H), 3.26 (t, J=6.1, 2H), 2.97 (t, J=6.1,2H), 2.12-1.64 (m, 8H).

Example 192-Cyclopentyl-4-(4-methoxy-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

Example 204-(2-Cyclopentyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yl)-benzonitrile

Example 214-(4-Fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidinehydrochloride

MS (ESI): exact mass calcd. for C₁₆H₁₈FN₃, 271.15; m/z found, 272.4[M+H]⁺. ¹H NMR (MeOH-d₄): 7.75-7.70 (m, 2H), 7.37-7.31 (m, 2H), 4.47 (s,2H), 3.72-3.68 (m, 2H), 3.37-3.32 (m, 2H), 3.30-3.22 (m, 1H), 1.39 (d,J=6.9, 6H).

Example 224-(4-Fluoro-phenyl)-2-isopropyl-6-methyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

Example 234-(3,4-Dichloro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidinehydrochloride

MS (ESI): exact mass calcd. for C₁₆H₁₇Cl₂N₃, 321.08; m/z found, 322.3[M+H]⁺. ¹H NMR (MeOH-d₄): 7.86-7.84 (m, 1H), 7.77-7.74 (m, 1H),7.60-7.57 (m, 1H), 4.47 (s, 2H), 3.71-3.67 (m, 2H), 3.35-3.32 (m, 2H),3.29-3.21 (m, 1H), 1.38 (d, J=6.9, 6).

Example 244-(3,4-Difluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidinehydrochloride

MS (ESI): exact mass calcd. for C₁₆H₁₇F₂N₃, 289.14; m/z found, 290.4[M+H]⁺. ¹H NMR (MeOH-d₄): 7.67-7.62 (m, 1H), 7.54-7.47 (m, 2H), 4.48 (s,2H), 3.71-3.67 (m, 2H), 3.35-3.32 (m, 2H), 3.29-3.21 (m, 1H), 1.38 (d,J=6.9, 6H).

Example 254-(3-Fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

Example 264-(2-Fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

Example 274-(2,4-Difluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

Example 282-Isopropyl-4-p-tolyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

Example 294-(4-Chloro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

Example 302-Isopropyl-4-(4-methoxy-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

Example 312-Isopropyl-4-phenyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

Example 322-Isopropyl-4-(4-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

Example 332-Isopropyl-4-(2-phenoxy-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

Example 342-Isobutyl-4-thiophen-3-yl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

MS (ESI): exact mass calcd. for C₁₅H₁₉N₃S, 273.13; m/z found, 274.1[M+H]⁺. ¹H NMR (CDCl₃): 7.67 (dd, J=1.3, 2.9, 1H), 7.52 (dd, J=1.3, 5.0,1H), 7.40 (dd, J=2.9, 5.0, 1H), 4.11 (s, 2H), 3.2 (t, J=6.1, 2H), 2.96(t, J=6.1, 2H), 2.80 (d, J=7.3, 2H), 2.35-2.25 (m, 1H), 0.98 (d, J=6.7,6H).

Example 352-Isobutyl-4-thiophen-2-yl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

MS (ESI): exact mass calcd. for C₁₅H₁₉N₃S, 273.13; m/z found, 274.1[M+H]⁺. ¹H NMR (CDCl₃): 7.52 (dd, J=1.0, 5.1, 1H), 7.48 (dd, J=1.0, 3.8,1H), 7.16 (dd, J=3.8, 5.1, 1H), 4.22, (s, 2H), 3.27 (t, J=6.0, 2H), 2.96(t, J=6.0, 2H), 2.78 (d, J=7.3, 2H), 2.36-2.26 (m, 1H), 0.99 (d, J=6.7,6H).

Example 362-Isobutyl-4-pyridin-4-yl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

MS (ESI): exact mass calcd. for C₁₆H₂₀N₄, 268.17; m/z found, 269.2[M+H]⁺. ¹H NMR (CDCl₃): 8.75-8.74 (m, 2H), 7.44-7.43 (m, 2H), 3.97 (s,2H), 3.28 (t, J=6.0, 2H), 3.01 (t, J=6.0, 2H), 2.83 (d, J=7.3, 2H),2.34-2.23 (m, 1H), 0.98 (d, J=6.7, 6H).

Example 374-(4-Fluoro-phenyl)-2-isobutyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

Example 382-Isobutyl-4-p-tolyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

Example 394-(4-Fluoro-3-methyl-phenyl)-2-isobutyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

Example 404-(2-Isobutyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yl)-benzonitrile

Example 412-Isobutyl-4-(4-methoxy-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

Example 422-sec-Butyl-4-(2-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidinehydrochloride

MS (ESI): exact mass calcd. for C₁₇H₂₀FN₃, 285.16; m/z found, 286.4[M+H]⁺. ¹H NMR (DMSO-d₆): 9.62 (s, 2H), 7.66-7.61 (m, 1H), 7.51-7.39 (m,3H), 4.08-4.06 (m, 2H), 3.55-3.47 (m, 2H), 3.17 (dd, J=6.3, 2H), 2.93(tq, J=6.9, 7.4, 1H), 1.86-1.75 (m, 1H), 1.66-1.55 (m,1H), 1.25 (d,J=6.9, 3H), 0.82 (t, J=7.4, 3H).

Example 432-sec-Butyl-4-(3-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

Example 442-sec-Butyl-4-(4-methoxy-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

Example 452-sec-Butyl-4-(4-trifluoromethoxy-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

The following Examples 46-57 were prepared as described in Examples 1and 2, substituting 5-oxo-azepane-1,4-dicarboxylic acid 1-tert-butylester 4-ethyl ester (J. Het. Chem. 1992, 29(4), 779-786) for4-oxo-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester.

Example 462-Cyclopentyl-4-(4-fluoro-phenyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine

MS (ESI): exact mass calcd. for C₁₉H₂₂FN₃, 311.18; m/z found, 312.4[M+H]⁺. ¹H NMR (CDCl₃): 7.46 (dd, J=5.4, 8.6, 2H), 7.14 (dd, J=8.7, 2H),3.32-3.26 (m, 1H), 3.18-3.16 (m, 2H), 3.07-3.05 (m, 2H), 2.96-2.92 (m,4H), 2.12-2.06 (m, 2H), 1.99-1.91 (m, 2H), 1.87-1.80 (m, 2H), 1.72-1.64(m, 2H).

Example 472-Cyclopentyl-4-p-tolyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine

MS (ESI): exact mass calcd. for C₂₀H₂₅N₃, 307.2; m/z found, 308.4[M+H]⁺. ¹H NMR (CDCl₃): 7.37 (d, J=8.1, 2H), 7.26 (m, 2H), 3.32-3.26 (m,1H), 3.17-3.15 (m, 2H), 3.07-3.05 (m, 2H), 2.94 (m, 4H), 2.41 (s, 3H),2.11-2.05 (m, 2H), 2.0-1.93 (m, 2H), 1.86-1.79 (m, 2H), 1.71-1.62 (m,2H).

Example 482-Cyclopentyl-4-(4-methoxy-phenyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine

MS (ESI): exact mass calcd. for C₂₀H₂₅N₃O, 323.2; m/z found, 324.5[M+H]⁺. ¹H NMR (CDCl₃): 7.44 (d, J=8.9, 2H), 6.98 (d, J=8.9, 2H), 3.86(s, 3H), 3.35-3.26 (m, 1H), 3.17-3.15 (m, 2H), 3.07-3.05 (m, 2H),2.12-2.05 (m, 2H), 2.00-1.92 (m, 2H), 1.87-1.80 (m, 2H), 1.71-1.64 (m,2H).

Example 494-(2-Cyclopentyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl)-benzonitrile

Example 504-(4-Fluoro-phenyl)-2-isopropyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepinehydrochloride

MS (ESI): exact mass calcd. for C₁₇H₂₀FN₃, 285.16; m/z found, 286.2[M+H]⁺. ¹H NMR (MeOH-d₄): 7.76-7.71 (m, 2H), 7.41-7.36 (m, 2H),3.69-3.65 (m, 2H), 3.63-3.59 (m, 2H), 3.49-3.45 (m, 2H), 3.42-3.34 (m,3H), 1.45 (d, J=6.9, 6H).

Example 514-(4-Chloro-phenyl)-2-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine

Example 522-Methyl-4-phenyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine

Example 534-(3-Chloro-phenyl)-2-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine

Example 542-Benzyl-4-(4-fluoro-phenyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine

MS (ESI): exact mass calcd. for C₂₁H₂₀FN₃, 333.16; m/z found, 334.4[M+H]⁺. ¹H NMR (CDCl₃): 7.44-7.42 (m, 4H), 7.31-7.28 (m, 2H), 7.23-7.20(m, 1H), 7.16-7.13 (m, 2H), 4.25 (s, 2H), 3.18-3.16 (m, 2H), 3.06-3.03(m, 2H), 2.94-2.90 (m, 4H).

Example 552-Benzyl-4-p-tolyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine

MS (ESI): exact mass calcd. for C₂₂H₂₃N₃, 329.19; m/z found, 330.5[M+H]⁺. ¹H NMR (CDCl₃): 7.45-7.43 (m, 2H), 7.35-7.33 (m, 2H), 7.30-7.25(m, 4H), 7.22-7.19 (m, 1H), 4.25 (s, 2H), 3.17-3.15 (m, 2H), 3.05-3.03(m, 2H), 2.41 (s, 3H).

Example 562-Benzyl-4-(4-trifluoromethyl-phenyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine

MS (ESI): exact mass calcd. for C₂₂H₂₀F₃N₃, 383.16; m/z found, 384.4[M+H]⁺. ¹H NMR (CDCl₃): 7.72 (d, J=8.1, 2H), 7.55 (d, J=8.0, 2H), 7.43(d, J=7.5, 2H), 7.31-7.28 (m, 2H), 7.23-7.20 (m, 1H), 4.26 (s, 2H),3.20-3.18 (m, 2H), 3.06-3.04 (m, 2H), 2.95-2.93 (m, 2H), 2.90-2.88 (m,2H).

Example 572-(4-Fluoro-benzyl)-4-(4-fluoro-phenyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine

MS (ESI): exact mass calcd. for C₂₁H₁₉F₂N₃, 351.15; m/z found, 352.4[M+H]⁺. ¹H NMR (CDCl₃): 7.44-7.41 (m, 2H), 7.40-7.36 (m, 2H), 7.18-7.12(m, 2H), 7.01-6.95 (m, 2H), 4.21 (s, 2H), 3.19-3.17 (m, 2H), 3.07-3.04(m, 2H), 2.96-2.92 (m, 4H).

Example 582-Cyclopentyl-4-(4-fluoro-phenyl)-7-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine

To a solution of2-cyclopentyl-4-(4-fluoro-phenyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine(0.035 g, 0.112 mmol) in MeOH (1 mL) was added formaldehyde (37% inwater; 0.10 mL) and NaBH(OAc)₃ (0.032 g, 0.151 mmol). After the reactionwas judged complete, the mixture was diluted with 1 N NaOH and extractedwith CH₂Cl₂ (3×). The combined organic layers were dried andconcentrated. The resulting residue was purified via SiO₂ chromatography(1-7% 2 M NH₃ in MeOH/CH₂Cl₂) to give 0.031 g (87%) of the titlecompound. MS (ESI): exact mass calcd. for C₂₀H₂₄FN₃, 325.20; m/z found,326.4 [M+H]⁺. ¹H NMR (CDCl₃): 7.47 (dd, J=5.4, 8.8, 2H), 7.15 (t, J=8.7,2H), 3.38-3.30 (m, 1H), 3.20 (dd, J=4.1, 6.3, 2H), 2.97 (dd, J=4.2, 5.9,2H), 2.71-2.70 (m, 2H), 2.60 (m, 2H), 2.41 (s, 3H), 2.12-2.05 (m, 2H),1.99-1.91 (m, 2H), 1.87-1.79 (m, 2H), 1.73-1.63 (m, 2H).

The following compounds in Examples 59-62 were prepared using methodssimilar to those described in Example 58, starting with thecorresponding unmethylated azepines from the preceding examples.

Example 592-Cyclopentyl-7-methyl-4-p-tolyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine

MS (ESI): exact mass calcd. for C₂₁H₂₇N₃, 321.22; m/z found, 322.5[M+H]⁺. ¹H NMR (CDCl₃): 7.39-7.37 (m, 2H), 7.27-7.25 (m, 2H), 3.35-3.26(m, 1H), 3.20-3.18 (m, 2H), 3.0-2.97 (m, 2H), 2.7-2.68 (m, 2H), 2.59 (m,2H), 2.41 (s, 3H), 2.40 (s, 3H), 2.12-2.04 (m, 2H), 2.0-1.91 (m, 2H),1.88-1.79 (m, 2H), 1.72-1.61 (m, 2H).

Example 602-Cyclopentyl-4-(4-methoxy-phenyl)-7-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine

MS (ESI): exact mass calcd. for C₂₁H₂₇N₃O, 337.22; m/z found, 338.5[M+H]⁺. ¹H NMR (CDCl₃): 7.44 (d, J=8.8, 2H), 6.98 (d, J=8.8, 2H), 3.86(s, 3H), 3.34-3.26 (m, 1H), 3.19 (dd, J=4.2, 6.2, 2H), 3.01 (dd, J=4.3,5.5, 2H), 2.71-2.69 (m, 2H), 2.61 (m, 2H), 2.41 (s, 3H), 2.12-2.05 (m,2H), 2.0-1.91 (m, 2H), 1.87-1.79 (m, 2H), 1.71-1.63 (m, 2H).

Example 612-Benzyl-7-methyl-4-p-tolyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine

MS (ESI): exact mass calcd. for C₂₃H₂₅N₃, 343.2; m/z found, 344.5[M+H]⁺. ¹H NMR (CDCl₃): 7.43 (d, J=7.3, 2H), 7.35 (d, J=8.0, 2H),7.30-7.25 (m, 4H), 7.21-7.19 (m, 1H), 4.26 (s, 2H), 3.18-3.16 (m, 2H),2.97-2.95 (m, 2H), 2.66-2.65 (m, 2H), 2.56 (m, 2H), 2.41 (s, 3H), 2.38(s, 3H).

Example 622-(4-Fluoro-benzyl)-4-(4-fluoro-phenyl)-7-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine

MS (ESI): exact mass calcd. for C₂₂H₂₁F₂N₃, 365.17; m/z found, 366.4[M+H]⁺. ¹H NMR (CDCl₃): 7.46-7.42 (m, 2H), 7.39-7.36 (m, 2H), 7.18-7.13(m, 2H), 7.0-6.95 (m, 2H), 4.22 (s, 2H), 3.20-3.17 (m, 2H), 2.96-2.93(m, 2H), 2.67-2.65 (m, 2H), 2.58-2.55 (m, 2H), 2.39 (s, 3H).

Example 632-(4-Fluoro-benzyl)-4-(4-fluoro-phenyl)-7-methyl-9-methylene-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine

To a solution of2-(4-fluoro-benzyl)-4-(4-fluoro-phenyl)-5,6,8,9-tetrahydro-pyrimido[4,5-d]azepine-7-carboxylicacid tert-butyl ester in formic acid was added paraformaldehyde (10equiv.). The mixture was heated at 80° C. for 6 h. The mixture wasdiluted with water and basified to pH ˜10 with 1 M NaOH. The mixture wasextracted with CH₂Cl₂, dried and concentrated. Chromatography on SiO₂(0-5% 2 M NH₃ in MeOH/CH₂Cl₂) afforded the desired compound.2-(4-Fluoro-benzyl)-4-(4-fluoro-phenyl)-7-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepinewas also obtained. MS (ESI): exact mass calcd. for C₂₃H₂₁F₂N₃, 377.17;m/z found, 378.4 [M+H]⁺. ¹H NMR (CDCl₃): 7.50-7.46 (m, 2H), 7.42-7.37(m, 2H), 7.17-7.12 (m, 2H), 6.99-6.94 (m, 4H), 6.03-6.01 (m, 1H),5.47-5.46 (m, 1H), 4.25 (s, 2H), 3.51 (s, 2H), 2.87-2.83 (m, 2H),2.76-2.72 (m, 2H), 2.41 (s, 3H).

Example 642-Benzyl-4-(4-fluoro-phenyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepinehydrochloride

Step A. 3-Oxo-azepane-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethylester and 4-oxo-azepane-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethylester. To a 0° C. solution of 3-oxo-piperidine-1-carboxylic acidtert-butyl ester (11.3 g, 56.7 mmol) in Et₂O (170 mL) was added BF₃.Et₂O(7.2 mL, 56.7 mmol) and ethyl diazoacetate (7.2 mL, 68.0 mmol) dropwiseover 30 min. After an additional 1 h, satd. aq. NaHCO₃ was added and thesolution was stirred for 1 h, then was extracted with Et₂O (2×). Thecombined organic layers were washed with brine, dried and concentrated.The resulting residue was purified via SiO₂ chromatography (10-30%EtOAc/hexanes) to give 5.48 g (34%) of 3-oxo-azepane-1,4-dicarboxylicacid 1-tert-butyl ester 4-ethyl ester. In addition, 5.25 g (32%) of themore polar 4-oxo-azepane-1,3-dicarboxylic acid 1-tert-butyl ester3-ethyl ester was isolated.

Step B.2-Benzyl-4-(4-fluoro-phenyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepine.The title compound was prepared from 3-oxo-azepane-1,4-dicarboxylic acid1-tert-butyl ester 4-ethyl ester according to the methods described inExample 1. MS (ESI): exact mass calcd. for C₂₁H₂₀FN₃, 333.16; m/z found,334.4 [M+H]⁺. ¹H NMR (DMSO-d₆): 9.81 (m, 2H), 7.55 (dd, J=5.5, 8.7, 2H),7.40-7.35 (m, 4H), 7.31-7.27 (m, 2H), 7.22-7.19 (m, 1H), 4.46-4.43 (m,2H), 4.21 (s, 2H), 3.43-3.33 (m, 2H), 3.00-2.93 (m, 2H), 1.98-1.88 (m,2H).

The following compounds in Examples 65-68 were prepared using methodssimilar to those described in Example 64.

Example 654-(4-Fluoro-phenyl)-2-isopropyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepinehydrochloride

MS (ESI): exact mass calcd. for C₁₇H₂₀FN₃, 285.16; m/z found, 286.4[M+H]⁺. ¹H NMR (DMSO-d₆): 9.77 (s, 2H), 7.57 (dd, J=5.5, 8.7, 2H),7.40-7.37 (m, 2H), 4.49-4.44 (m, 2H), 3.43-3.36 (m, 2H), 3.19-3.10 (m,1H), 2.99-2.97 (m, 2H), 1.99-1.92 (m, 2H), 1.30 (d, J=6.9, 6H).

Example 662-Isopropyl-4-p-tolyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepinehydrochloride

MS (ESI): exact mass calcd. for C₁₈H₂₃N₃, 281.19; m/z found, 282.4[M+H]⁺. ¹H NMR (DMSO-d₆): 9.80 (s, 2H), 7.41 (d, J=8.0, 2H), 7.35 (d,J=8.0, 2H), 4.46 (m, 2H), 3.50-3.36 (m, 2H), 3.18-3.10 (m, 1H),3.90-2.98 (m, 2H), 2.8 (s, 3H), 1.98-1.90 (m, 2H), 1.29 (d, J=6.9, 6H).

Example 672-Isopropyl-4-(4-methoxy-phenyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepine

Example 682-Isopropyl-4-phenyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepine

Example 692-Benzyl-4-(4-fluoro-phenyl)-6,7,8,9-tetrahydro-5H-1,3,6-triaza-benzocycloheptenehydrochloride

The title compound was synthesized as described in Example 64 using4-oxo-azepane-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester. MS(ESI): exact mass calcd. for C₂₁H₂₀FN₃, 333.16; m/z found, 334.4 [M+H]⁺.¹H NMR (DMSO-d₆): 9.59 (s, 2H), 7.66 (dd, J=5.5, 8.8, 2H), 7.42-7.27 (m,6H), 7.22-7.19 (m, 1H), 4.29-4.26 (m, 2H), 4.21 (s, 2H), 3.42-0.36 (m,2H), 3.22-3.20 (m, 2H), 2.01-1.95 (m, 2H).

Example 702,7-Dibenzyl-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidinehydrochloride

The title compound was synthesized as described in Example 1, Steps A-C,using 1-benzyl-3-oxo-piperidine-4-carboxylic acid ethyl esterhydrochloride. Purification was performed using SiO₂ chromatography (2 MNH₃ in MeOH/CH₂Cl₂). MS (ESI): exact mass calcd. for C₂₇H₂₄FN₃, 409.2;m/z found, 410.5 [M+H]⁺. ¹H NMR (MeOH-d₄): 7.74-7.70 (m, 2H), 7.66-7.63(m, 2H), 7.56-7.53 (m, 3H), 7.36-7.18 (m, 7H), 4.59 (s, 2H), 4.49 (br s,2H), 4.29 (s, 2H).

The compounds in Examples 71-75 were prepared using methods similar tothose described in Example 70.

Example 712,7-Dibenzyl-4-p-tolyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine

Example 722,7-Dibenzyl-4-phenyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine

Example 732,7-Dibenzyl-4-(4-methoxy-phenyl)-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine

Example 747-Benzyl-4-(4-fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine

Example 757-Benzyl-2-isopropyl-4-phenyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine

Example 762-Benzyl-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidinehydrochloride

To a solution of2,7-dibenzyl-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidinehydrochloride in EtOH was added 10% Pd/C (1 equiv) followed by1,4-cyclohexadiene (5 equiv). The mixture was heated at 85° C. for 5 h,filtered and concentrated. The residue was dissolved in CH₂Cl₂ andtreated with Dowex 550A resin. After 1 h, the resin was removed byfiltration and the filtrate was concentrated. Chromatography on SiO₂ (2M NH₃ in MeOH/CH₂Cl₂) afforded the title compound. MS (ESI): exact masscalcd. for C₂₀H₁₈FN₃, 319.15; m/z found, 320.4 [M+H]⁺. ¹H NMR (MeOH-d₄):7.70-7.67 (m, 2H), 7.36-7.35 (m, 2H), 7.31-7.25 (m, 4H), 7.20-7.17 (m,1H), 4.42 (s, 2H), 4.26 (s, 2H), 3.48 (t, J=6.1, 2H), 3.09 (t, J=6.1,2H).

The compounds in Examples 77-81 were prepared using methods similar tothose described in Example 76.

Example 77 2-Benzyl-4-p-tolyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidinehydrochloride

MS (ESI): exact mass calcd. for C₂₁H₂₁N₃, 315.17; m/z found, 316.4[M+H]⁺. ¹H NMR (MeOH-d₄): 7.55-7.54 (m, 2H), 7.44-7.36 (m, 4H),7.29-7.26 (m, 2H), 7.22-7.19 (m, 1H), 4.46 (s, 2H), 4.29 (s, 2H), 3.48(t, J=6.1, 2H), 3.12 (t, J=6.1, 2H), 2.44 (s, 3H).

Example 78 2-Benzyl-4-phenyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine

Example 792-Benzyl-4-(4-methoxy-phenyl)-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine

Example 804-(4-Fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidinehydrochloride

MS (ESI): exact mass calcd. for C₁₆H₁₈FN₃, 271.15; m/z found, 272.4[M+H]⁺. ¹H NMR (MeOH-d₄): 7.74-7.72 (m, 2H), 7.33-7.30 (m, 2H), 4.48 (s,2H), 3.51 (t, J=6.0, 2H), 3.26-3.20 (m, 1H), 3.12 (t, J=6.0, 2H), 1.37(d, J=7.2, 6H).

Example 812-Isopropyl-4-phenyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine

The compounds in Examples 82-85 were prepared using methods similar tothose described in Example 58.

Example 822-Benzyl-4-(4-fluoro-phenyl)-7-methyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidinehydrochloride

MS (ESI): exact mass calcd. for C₂₁H₂₀FN₃, 333.16; m/z found, 334.4[M+H]⁺. ¹H NMR (MeOH-d₄): 7.70-7.68 (m, 2H), 7.36-7.17 (m, 7H),4.70-4.60 (m, 1H), 4.45-4.35 (m, 1H), 4.25 (s, 2H), 3.76 (br s, 1H),3.11-3.01 (m, 4H).

Example 832-Benzyl-4-(4-fluoro-phenyl)-7-isopropyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine

Example 844-(4-Fluoro-phenyl)-2-isopropyl-7-methyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidinehydrochloride

MS (ESI): exact mass calcd. for C₁₇H₂₀FN₃, 285.16; m/z found, 286.3[M+H]⁺. ¹H NMR (MeOH-d₄): 7.74-7.71 (m, 2H), 7.32-7.29 (m, 2H),4.72-4.62 (m, 1H), 4.49-4.37 (m, 1H), 3.79 (br s, 1H), 3.43-3.32 (m,2H), 3.25-3.19 (m, 1H), 3.13 (s, 3H), 3.09-2.99 (m, 1H), 1.35 (d, J=6.6,6H).

Example 852-Isopropyl-7-methyl-4-phenyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine

Example 867-Benzyl-2-isopropyl-4-(5-methyl-thiophen-3-yl)-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidinehydrochloride

Step A.4-(7-Benzyl-2-isopropyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yl)-thiophene-2-carbaldehyde.The title compound was prepared as described in Example 1, Steps A-C.

Step B.7-Benzyl-2-isopropyl-4-(5-methyl-thiophen-3-yl)-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine.To a solution of the product of Step A (0.230 g) in ethylene glycol wasadded hydrazine hydrate (0.1 mL). The mixture was heated at 200° C. for1 h, then KOH (0.150 g) was added and the heating continued for 6 h. Themixture was allowed to cool then was diluted with water and extractedwith Et₂O. The combined organic extracts were dried and concentrated to0.210 g of pale yellow solid. Chromatography on SiO₂ (EtOAc/hexanes)afforded 0.146 g of the title compound. MS (ESI): exact mass calcd. forC₂₂H₂₅N₃S, 363.18; found m/z 364.4 [M+H]⁺. ¹H NMR (MeOH-d₄): 7.85-7.84(m, 1H), 7.65-7.63 (m, 2H), 7.56-7.55 (m, 3H), 7.37-7.36 (m, 1H), 4.60(br s, 2H), 4.44 (br s, 2H), 3.46-3.32 (m, 2H), 3.22-3.17 (m, 1H), 2.55(s, 3H), 1.34 (d, J=7.2, 6H).

Example 877-Benzyl-2-isopropyl-4-thiophen-3-yl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidinehydrochloride

The title compound was prepared according to the methods described inExample 86. MS (ESI): exact mass calcd. for C₂₁H₂₃N₃S, 349.16; m/zfound, 350.4 [M+H]⁺. ¹H NMR (MeOH-d₄): 8.29-8.28 (m, 1H), 7.72-7.69 (m,4H), 7.56-7.55 (m, 3H), 4.65 (s, 2H), 4.59 (br s, 2H), 3.89 (br s, 1H),3.57-3.32 (m, 4H), 1.40 (d, J=6.6, 6H).

Example 882-Isopropyl-4-(5-methyl-thiophen-3-yl)-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidinehydrochloride

A solution of7-benzyl-2-isopropyl-4-(5-methyl-thiophen-3-yl)-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidinehydrochloride (0.133 g) in 1,2-dichloroethane (7 mL) was treated with1-chloroethylchloroformate (0.105 mL). The mixture was heated at 95° C.for 16 h, concentrated, dissolved in MeOH, and heated at 50° C. for anadditional 2 h. The mixture was concentrated and chromatographed on SiO₂(2 M NH₃ in MeOH/CH₂Cl₂). MS (ESI): exact mass calcd. for C₁₅H₁₉N₃S,273.13; m/z found, 274.3 [M+H]⁺. ¹H NMR (MeOH-d₄): 7.81-7.80 (m, 1H),7.36-7.35 (m, 1H), 4.42 (s, 2H), 3.55 (t, J=6.0, 2H), 3.25 (t, J=6.0,2H), 3.19 (m, 1H), 2.55 (s, 3H), 1.35 (d, J=7.2, 6H).

Example 892-Isopropyl-4-thiophen-3-yl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidinehydrochloride

The title compound was prepared according to the methods described inExample 88. MS (ESI): exact mass calcd. for C₁₄H₁₇N₃S, 259.11; m/zfound, 260.3 [M+H]⁺. ¹H NMR (MeOH-d₄): 8.16-8.15 (m, 1H), 7.70-7.65 (m,2H), 4.49 (s, 2H), 3.57 (t, J=6.0, 2H), 3.31-3.23 (m, 3H), 1.39 (d,J=7.2, 6H).

The following Examples 90-91 were prepared using methods similar tothose described in Example 58.

Example 902-Isopropyl-7-methyl-4-(5-methyl-thiophen-3-yl)-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidinehydrochloride

MS (ESI): exact mass calcd. for C₁₆H₂₁N₃S, 287.15; m/z found, 288.3[M+H]⁺. ¹H NMR (MeOH-d₄): 7.79 (s, 1H), 7.36 (s, 1H), 4.65-4.54 (m, 1H),4.45-4.35 (m, 1H), 3.83 (br s, 1H), 3.41 (br s, 1H), 3.27 (br s, 1H),3.20-3.13 (m, 4H), 2.55 (s, 3H), 1.34 (d, J=7.2, 6H).

Example 912-Isopropyl-7-methyl-4-thiophen-3-yl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidinehydrochloride

MS (ESI): exact mass calcd. for C₁₅H₁₉N₃S, 273.13; m/z found, 274.3[M+H]⁺. ¹H NMR (MeOH-d₄): 8.27 (t, J=1.8, 1H), 7.71 (d, J=1.8, 2H),4.82-4.71 (m, 1H), 4.63-4.49 (m, 1H), 3.95-3.81 (m, 1H), 3.57-3.41 (m,1H), 3.34-3.32 (m, 1H), 3.16 (s, 3H), 1.41 (d, J=6.6, 6H).

The following compounds in Examples 92-99 were prepared using themethods similar to those described for Example 70 utilizing1-benzyl-5-methyl-4-oxo-piperidine-3-carboxylic acid ethyl ester inplace of 1-benzyl-3-oxo-piperidine-4-carboxylic acid ethyl esterhydrochloride.

Example 926-Benzyl-4-(4-fluoro-phenyl)-2-isopropyl-8-methyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

Example 936-Benzyl-4-(3-chloro-4-fluoro-phenyl)-2-isopropyl-8-methyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

Example 946-Benzyl-2-isopropyl-8-methyl-4-p-tolyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

Example 956-Benzyl-2-isopropyl-8-methyl-4-phenyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

Example 966-Benzyl-2-isopropyl-8-methyl-4-(4-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

Example 976-Benzyl-4-(4-chloro-phenyl)-2-isopropyl-8-methyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

Example 986-Benzyl-2-isopropyl-8-methyl-4-thiophen-3-yl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

Example 996-Benzyl-4-(4′-chloro-biphenyl-4-yl)-2-isopropyl-8-methyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

The following compounds in Examples 100-105 were prepared using methodssimilar to those described in Example 76.

Example 1004-(4-Fluoro-phenyl)-2-isopropyl-8-methyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidinehydrochloride

MS (ESI): exact mass calcd. for C₁₇H₂₀FN₃, 285.16; m/z found, 286.4[M+H]⁺. ¹H NMR (MeOH-d₄): 7.69-7.66 (m, 2H), 7.34-7.30 (m, 2H),4.56-4.53 (m,1H), 4.32-4.29 (m, 1H), 3.81-3.78 (m,1H), 3.45-3.38 (m,1H),3.36-3.30 (m,1H), 3.26-3.24 (m, 1H), 1.55 (d, J=7.2, 3H), 1.37 (d,J=6.6, 6H).

Example 1014-(3-Chloro-4-fluoro-phenyl)-2-isopropyl-8-methyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidinehydrochloride

MS (ESI): exact mass calcd. for C₁₇H₁₉ClFN₃, 319.13; m/z found, 320.3[M+H]⁺. ¹H NMR (MeOH-d₄): 7.79-7.77 (m, 1H), 7.60-7.58 (m, 1H),7.46-7.44 (m, 1H), 4.56-4.54 (m, 1H), 4.32-4.29 (m, 1H), 3.80-3.77 (m,1H), 3.40-3.32 (m, 2H), 3.26-3.20 (m, 1H), 1.54 (d, J=7.2, 3H), 1.36 (d,J=7.2, 6H).

Example 1022-Isopropyl-8-methyl-4-p-tolyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidinehydrochloride

MS (ESI): exact mass calcd. for C₁₈H₂₃N₃, 281.19; m/z found, 282.4[M+H]⁺. ¹H NMR (MeOH-d4): 7.57-7.56 (m, 2H), 7.45-7.44 (m, 2H),4.59-4.56 (m,1H), 4.35-4.33 (m, 1H), 3.83-3.80 (m, 1H), 3.52-3.49 (m,1H), 3.40-3.30 (m, 2H), 2.46 (s, 3H), 1.58 (d, J=7.2, 3H), 1.41 (d,J=6.6, 6H).

Example 1032-Isopropyl-8-methyl-4-phenyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

Example 1042-Isopropyl-8-methyl-4-(4-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

Example 1052-Isopropyl-8-methyl-4-thiophen-3-yl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

Example 1064-(4-Fluoro-phenyl)-2-isopropyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidinehydrochloride

Step A.6-Benzyl-2-isopropyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-ol. To asolution of 1-benzyl-4-oxo-pyrrolidine-3-carboxylic acid ethyl esterhydrochloride (U.S. Pat. No. 3,312,716; 0.568 g, 2.30 mmol) in tert-BuOHwas added isobutyramidine hydrochloride (0.282 g, 2.30 mmol) and KOtBu(0.516 g, 4.6 mmol). After heating for 6 h at 100° C., the reaction wascooled to rt, concentrated, diluted with water and washed with Et₂O. Theorganic layer discarded. The aqueous layer was adjusted to pH 7 andextracted with Et₂O. The organic layers were then dried and concentratedto give 0.145 g (23%) of the title compound of yellow solid that wasused without further purification.

Steps B and C. The title compound was prepared according to the methodsdescribed in Example 1, Steps B and C. MS (ESI): exact mass calcd. forC₂₂H₂₂FN₃, 347.18; m/z found, 348.3 [M+H]⁺. ¹H NMR (MeOH-d₄): 7.99-7.96(m, 2H), 7.61-7.60 (m, 2H), 7.53-7.51 (m, 3H), 7.34-7.32 (m, 2H), 5.09(br s, 2H), 4.71 (br s, 4H), 3.31-3.25 (m, 1H), 1.38 (d, J=7.2, 6H).

Example 1074-(4-Fluoro-phenyl)-2-isopropyl-7-pyrrolidin-1-yl-5,6,7,8-tetrahydro-quinazoline

Step A. 4-Ethoxy-2-oxo-cyclohex-3-enecarboxylic acid ethyl ester. To a−78° C. solution of LDA (192 mmol) in THF (200 mL) was added3-ethoxy-cyclohex-2-enone (23 mL) dropwise. After stirring for 1 h at−78° C., ethyl cyanoformate (16 mL) was added. The mixture was stirredat −78° C. for 4 h and then was warmed to rt and stirred for 1 h. Themixture was concentrated, diluted with aq. NH₄Cl (300 mL), and pouredinto water. The resulting solids were collected by suction filtrationand washed with hexanes followed by water, then was dried andconcentrated to provide 17.1 g of a brown solid. TLC (SiO₂, 33%EtOAc/hexanes): R_(f)=0.43.

Step B. 7-Oxo-1,4-dioxa-spiro[4,5]decane-8-carboxylic acid ethyl ester.To a solution of the product of Step A (25.4 g resulting from iterativereactions) in toluene (500 mL) was added ethylene glycol (8.5 mL) andp-TsOH (1.9 g). The mixture was heated at reflux for 4 h in a flaskfitted with a Dean-Stark trap. The mixture was then cooled andconcentrated. Chromatography on SiO₂ (0 to 15% EtOAc/hexanes) afforded7.76 g of the desired compound. TLC (SiO₂, 25% EtOAc/hexanes):R_(f)=0.42.

Step C.2-Isopropyl-7-(2-[1,3]dioxolane)-5,6,7,8-tetrahydro-quinazolin-4-ol. Thetitle compound was prepared according to the method described in Example1, Step A. MS (ESI): exact mass calcd. for C₁₃H₁₈N₂O₃, 250.13; m/zfound, 251.3 [M+H]⁺.

Step D. Trifluoro-methanesulfonic acid2-isopropyl-7-(2-[1,3]Dioxolane)-5,6,7,8-tetrahydro-quinazolin-4-ylester. The title compound was prepared according to the method describedin Example 1, Step B. TLC (SiO₂, 25% EtOAc/hexanes): R^(f)=0.46. MS(ESI): exact mass calcd. for C₁₄H₁₇F₃N₂O₅S, 382.08; m/z found, 383.2[M+H]⁺.

Step E.4-(4-Fluoro-phenyl)-2-isopropyl-7-(2-[1,3]dioxolane)-5,6,7,8-tetrahydro-quinazoline.The title compound was prepared according to the method described inExample 1, Step C. TLC (SiO₂, 25% EtOAc/hexanes): R_(f)=0.40. MS (ESI):exact mass calcd. for C₁₉H₂₁ FN₂O₂, 328.16; m/z found, 329.3 [M+H]⁺.

Step F. 4-(4-Fluoro-phenyl)-2-isopropyl-5,8-dihydro-6H-quinazolin-7-one.To a solution of the product of Step E (1.15 g) in THF (70 mL) was added1 M HCl (6 mL). The mixture was heated at 60° C. for 10 h, cooled to rt,and poured into 350 mL of water. The aqueous mixture was basified to pH˜9 with 1 M NaOH, and was extracted with CH₂Cl₂. The organic layer wasdried and concentrated to afford 0.98 g of the desired compound, whichwas used in the next step without purification. MS (ESI): exact masscalcd. for C₁₇H₁₇FN₂O, 284.13; m/z found, 285.3 [M+H]⁺.

Step G.4-(4-Fluoro-phenyl)-2-isopropyl-7-pyrrolidin-1-yl-5,6,7,8-tetrahydro-quinazoline.To a solution of the product of Step F (0.128 g) in MeOH (4 mL) wasadded of bromocresol green (0.003 g), pyrrolidine (0.06 mL), and NaBH₃CN(0.20 g). To this mixture was added 1 M HCl in MeOH until a persistentcolor change to yellow was observed. After 30 min, the mixture wasquenched with 1 M NaOH and poured into water (50 mL). The mixture wasextracted with CH₂Cl₂, dried and concentrated. Chromatography on SiO₂ (0to 5% 2 M NH₃ in MeOH/CH₂Cl₂) afforded 0.015 g of the desired compound.MS (ESI): exact mass calcd. for C₂₁H₂₆FN₃, 339.21; m/z found, 340.4[M+H]⁺. ¹H NMR (CDCl₃): 7.59-7.54 (m, 2H), 7.18-7.13 (m, 2H), 3.76-3.68(m, 1H), 3.50-3.44 (m, 1H), 3.41-3.35 (m, 1H), 3.28-3.14 (m, 2H),3.0-2.93 (m, 1H), 2.88-2.70 (m, 4H), 2.36-2.23 (m, 3H), 2.19-2.09 (m,1H), 1.98-1.87 (m, 2H).

Example 108[4-(4-Fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-quinazolin-7-yl]-methyl-aminehydrochloride

The title compound was prepared according to the method described forExample 107. MS (ESI): exact mass calcd. for C₁₈H₂₂FN₃, 299.18; m/zfound, 300.4 [M+H]⁺. ¹H NMR (MeOH-d₄): 7.80-7.72 (m, 2H), 7.37-7.30 (m,2H), 3.81-3.71 (m, 1H), 3.65-3.56 (m, 1H), 3.35-3.26 (m, 1H), 3.22-3.14(m, 1H), 3.11-3.00 (m, 1H), 2.99-2.91 (m, 1H), 2.85 (s, 3H), 2.42-2.33(m, 1H), 1.92-1.82 (m, 1H), 1.43-1.38 (m, 6H).

Example 109[4-(4-Fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-quinazolin-6-yl]-methyl-aminehydrochloride

The title compound was prepared according to the methods described forExample 107, using 1,4-dioxa-spiro[4.5]decan-8-one. MS (ESI): exact masscalcd. for C₁₈H₂₂FN₃, 299.18; m/z found, 300.4 [M+H]⁺. ¹H NMR (MeOH-d₄):7.87-7.82 (m, 2H), 7.40-7.35 (m, 2H), 3.59-3.52 (m, 1H), 3.41-3.24 (m,4H), 3.20-3.13 (m, 1H), 2.76 (s, 3H), 2.54-2.47 (m, 1H), 2.21-2.11 (m,1H), 1.45 (d, J=6.9, 3H), 1.44 (d, J=6.9, 3H).

Example 1104-(4-Fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-quinazolin-7-ol

To a solution of4-(4-fluoro-phenyl)-2-isopropyl-5,8-dihydro-6H-quinazolin-7-one (0.126g) in EtOH (3 mL) was added NaBH₄ (0.053 g). After 16 h, the mixture wastreated with 1 M NaOH (5 mL) and water (10 mL). The mixture was stirredfor 30 min then extracted with CH₂Cl₂. The organic layer was dried andconcentrated. Chromatography on SiO₂ (10 to 35% EtOAc/hexanes) afforded0.98 g of the title compound. TLC (SiO₂, 50% EtOAc/hexanes): R_(f)=0.18.MS (ESI): exact mass calcd. for C₁₇H₁₉FN₂O, 286.15; m/z found, 287.3[M+H]⁺.

Example 1114-(4-Fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-quinazoline

The title compound was obtained as a minor product from thehydrogenation of of4-(4-fluoro-phenyl)-2-isopropyl-5,8-dihydro-6H-quinazolin-7-one with 10%Pd/C in the presence of pyrrolidine. MS (ESI): exact mass calcd. forC₁₇H₁₉FN₂, 270.15; m/z found, 271.3 [M+H]⁺. ¹H NMR (CDCl₃): 7.59-7.55(m, 2H), 7.16-7.12 (m, 2H), 3.21-3.13 (m, 1H), 2.95-2.91 (m, 2H),2.71-2.67 (m, 2H), 1.95-1.89 (m, 2H), 1.77-1.72 (m, 2H), 1.35 (d, J=6.9,6H).

Example 112 (2-Benzyl-6-p-tolyl-pyrimidin-4-ylmethyl)-dimethyl-amine

Step A.2-Benzyl-4-(tetrahydro-pyran-2-yloxymethyl)-6-p-tolyl-pyrimidine. To asolution of Pd(PPh₃)₂Cl₂ (0.285 g, 0.41 mmol) and CuI in THF (50 mL)(0.148 g, 0.777 mmol) was added Et₃N (1.5 mL, 11.0 mmol), p-toluoylchloride (1.3 mL, 10.0 mmol) and tetrahydro-2-(2-propynyloxy)-2H-pyran(1.4 mL, 10.0 mmol). After stirring for 2.5 h, a solution of2-phenylacetamidine hydrochloride (2.0 g, 11.7 mmol) in THF/MeOH (1:1,10 mL) was added followed by additional MeOH (5 mL) and Na₂CO₃ (3.2 g,30.0 mmol). The reaction mixture was heated at reflux for 15 h, cooledto rt, diluted with Et₂O and filtered through a small pad ofdiatomaceous earth. The filtrate was concentrated and purified via SiO₂chromatography (10-45% EtOAc/hexanes) to give 2.0 g (53%) of the titlecompound. ¹H NMR (CDCl₃): 8.02-8.00 (m, 2H), 7.68 (s, 1H), 7.46-7.44 (m,2H), 7.30-7.27 (m, 4H), 7.21-7.19 (m, 1H), 4.87 (d, J=14.7, 1H), 4.77(t, J=3.5, 1H), 4.62 (d, J=15.1, 1H), 4.31 (s, 2H), 3.91-3.86 (m, 1H),3.57-3.52 (m, 1H), 2.41 (s, 3H), 1.96-1.87 (m, 1H), 1.84-1.72 (m, 2H),1.66-1.55 (m, 3H).

Step B. (2-Benzyl-6-p-tolyl-pyrimidin-4-yl)-methanol. To a solution ofthe product from Step A (2.0 g, 5.3 g) in MeOH (30 mL) was addedp-TsOH.H₂O. After 18 h, the reaction was diluted with satd. aq. NaHCO₃and extracted with EtOAc (2×). The combined organic layers were driedand concentrated to give the 1.53 g (99%) of the title compound. MS(ESI): exact mass calcd. for C₁₉H₁₈N₂O, 290.14; m/z found, 291.4 [M+H]⁺.¹H NMR (CDCl₃): 8.00-7.98 (m, 2H), 7.45-7.43 (m, 3H), 7.32-7.28 (m, 4H),7.23-7.20 (m, 1H), 4.74 (d, J=4.8, 2H), 4.33 (s, 2H), 3.62 (t, J=5.1,1H), 2.42 (s, 3H).

Step C. (2-Benzyl-6-p-tolyl-pyrimidin-4-ylmethyl)-dimethyl-amine. To asolution of the product from Step B (0.102 g, 0.35 mmol) in CH₂Cl₂ (2mL) was added the Dess-Martin periodinane (0.228, 0.53 mmol). After 30min, the mixture was diluted satd. aq. NaHCO₃ and extracted with CH₂Cl₂(2×). The combined organic layers were dried, concentrated, and filteredthrough a small plug of SiO₂ (25% EtOAc in hexanes). The filtrate wasconcentrated to give 2-benzyl-6-p-tolyl-pyrimidine-4-carbaldehyde(0.55g, 54%). To a solution of this aldehyde in CH₂Cl₂ (3 mL) was addeddimethylamine (2 M in THF; 0.15 mL, 0.30 mmol) and NaBH(OAc)₃ (0.058 mg,0.27 mmol). After 15 h, the reaction was diluted with CH₂Cl₂ and washedwith 1 N NaOH. The aqueous layer was extracted with CH₂Cl₂ (1×). Thecombined organic layers were dried and concentrated. The resultingresidue was purified via SiO₂ chromatography (1-7% 2 M NH₃ inMeOH/CH₂Cl₂) to give 0.050 g (79%) of the title compound. MS (ESI):exact mass calcd. for C₂₁H₂₃N₃, 317.19; m/z found, 318.4 [M+H]⁺. ¹H NMR(CDCl₃): 8.02 (d, J=8.2, 2H), 7.66 (s, 1H), 7.22 (d, J=7.5, 2H),7.31-7.26 (m, 4H), 7.22-7.18 (m, 1H), 4.33 (s, 2H), 3.58 (s, 2H), 2.41(s, 3H), 2.32 (s, 6H).

The compounds in Examples 113-114 were prepared using methods similar tothose described in Example 112, with the appropriate substituentchanges.

Example 1132-Benzyl-4-(4-methyl-piperazin-1-ylmethyl)-6-p-tolyl-pyrimidine

MS (ESI): exact mass calcd. for C₂₄H₂₈N₄, 372.23; m/z found, 373.5[M+H]⁺. ¹H NMR (CDCl₃): 8.02-7.99 (m, 2H), 7.66 (s, 1H), 7.46-7.44 (m,2H), 7.31-7.27 (m, 4H), 7.22-7.18 (m, 1H), 4.32 (s, 2H), 3.66 (s, 2H),2.58-2.50 (m, 8H), 2.42 (s, 3H), 2.32 (s, 3H).

Example 114[6-(4-Fluoro-phenyl)-2-isopropyl-pyrimidin-4-ylmethyl]-methyl-amine

Prop-2-ynyl-carbamic acid tert-butyl ester was converted to[6-(4-fluoro-phenyl)-2-isopropyl-pyrimidin-4-ylmethyl]-methyl-carbamicacid tert-butyl ester using methods described in Example 112, Step A.This ester was deprotected according to the methods described in Example1, Step D, to provide the title compound. MS (ESI): exact mass calcd.for C₁₅H₁₈FN₃, 259.15; m/z found, 260.3 [M+H]⁺. ¹H NMR (DMSO-d₆): 9.45(s, 2H); 8.31-8.28 (m, 2H), 8.10 (s, 1H), 7.45-7.41 (m, 2H), 4.35 (t,J=6.0, 2H), 3.26-3.18 (m, 1H), 2.69 (t, J=5.4, 3H), 1.37 (d, J=6.9, 6H).

Example 115 2-(2-Benzyl-6-p-tolyl-pyrimidin-4-yl)-ethylamine

Step A and B. 2-(2-Benzyl-6-p-tolyl-pyrimidin-4-yl)-ethanol. The titlecompound was prepared from 2-(3-butynyloxy)tetrahydro-2H-pyran using themethods described in Example 112, Steps A and B. MS (ESI): exact masscalcd. for C₂₀H₂₀N₂O, 304.16; m/z found, 305.4 [M+H]⁺. ¹H NMR (CDCl₃):7.98 (d, J=8.2, 2H), 7.42-7.42 (m, 2H), 7.34-7.29 (m, 4H), 7.25-7.22 (m,1H), 4.31 (s, 2H), 3.98 (t, J=5.3, 2H), 2.97 (t, J=5.3, 2H), 2.42 (s,3H).

Step C. 4-(2-Azido-ethyl)-2-benzyl-6-p-tolyl-pyrimidine. To a 0° C.solution of the product of Step B (0.150 g, 0.493 mmol) in THF (2.5 mL)was added MsCl (0.042 mL, 0.54 mmol) followed by Et₃N (0.76 mL, 0.54mmol). After 1 h, EtOAc was added and the mixture washed with brine,dried and concentrated to give methanesulfonic acid2-(2-benzyl-6-p-tolyl-pyrimidin-4-yl)-ethyl ester (0.185 g). To asolution of this mesylate (0.120 g, 0.32 mmol) in DMF (1 mL) was addedsodium azide (0.105 g, 1.6 mmol). The flask was heated at 40° C. for 10h, then was cooled to rt, diluted with water, and extracted with EtOAc(3×). The combined organic layers were dried and concentrated. Theresulting residue was purified via SiO₂ chromatography (5-15%EtOAc/hexanes) to give 0.080 g (76%) of the title compound. MS (ESI):exact mass calcd. for C₂₀H₁₉N₅, 329.16; m/z found, 330.4 [M+H]⁺. ¹H NMR(CDCl₃): 7.98 (d, J=8.2, 2H), 7.46-7.43 (m, 2H), 7.38 (s, 1H), 7.32-7.28(m, 4H), 7.23-7.19 (m, 2H), 4.31 (s, 2H), 3.76 (t, J=6.8, 2H), 3.02 (t,J=6.8, 2H), 2.42 (s, 3H).

Step D. To a solution of the product of Step C (0.066 g, 0.2 mmol) inTHF (2 mL) was added PPh₃ (0.059 g, 2.2 mmol). After 18 h, water wasadded (0.10 mL) and the mixture was stirred for 48 h. The mixture wasdiluted with water and extracted with CH₂Cl₂ (2×). The combined organiclayers were dried and concentrated. The resulting residue was purifiedvia SiO₂ chromatography (5-15% EtOAc/hexanes) to give 0.060 g (99%) ofthe title compound. MS (ESI): exact mass calcd. for C₂₀H₂₁N₃, 303.17;m/z found, 304.4 [M+H]⁺. ¹H NMR (CDCl₃): 7.98-7.96 (m, 2H), 7.45-7.44(m, 2H), 7.36 (s, 1H), 7.32-7.28 (m, 4H), 7.23-7.19 (m, 1H), 4.31 (s,2H), 3.13 (t, J=6.5, 2H), 2.91 (t, J=6.5, 2H), 2.42 (s, 3H).

Example 116[2-(4-Fluoro-benzyl)-4-p-tolyl-pyrimidin-5-ylmethyl]-dimethyl-amine

Step A. 2-(4-Fluoro-benzyl)-4-p-tolyl-pyrimidine-5-carboxylic acid ethylester. To solution of 3-dimethylamino-2-(4-methyl-benzoyl)-acrylic acidethyl ester (Tetrahedron, 2002, 58, 8581-8589; 0.567 g, 2.15 mmol) inEtOH (10 mL) was added 2-(4-fluoro-phenyl)-acetamidine hydrochloride(0.405 g, 2.15 mmol) and Et₃N (0.90 mL, 6.5 mmol). The mixture washeated at reflux for 18 h, and then was diluted with water and extractedwith EtOAc (2×). The combined organic layers were dried andconcentrated. The resulting residue was purified via SiO₂ chromatography(5-20% EtOAc/hexanes) to give 0.560 g (74%) of the title compound. MS(ESI): exact mass calcd. for C₂₁H₁₉FN₂O₂, 350.14; m/z found, 351.4[M+H]⁺. ^(H) NMR (CDCl₃): 8.97 (s, 1H), 7.51 (d, J=8.2, 2H), 7.38-7.35(m, 2H), 7.27-7.26 (m, 2H), 7.01-6.97 (m, 2H), 4.32 (s, 2H), 4.23 (q,J=7.1, 2H), 2.42 (s, 3H), 1.16 (t, J=7.1, 3H).

Step B. [2-(4-Fluoro-benzyl)-4-p-tolyl-pyrimidin-5-yl]-methanol. To a 0°C. solution of the product from Step A (0.606 g, 1.73 mmol) in THF (8mL) was added DIBAL-H (1.5 M in toluene; 2.5 mL, 3.8 mmol). The mixturewas allowed to warm to rt, and was stirred for 18 h. The mixture wasdiluted with 20% aq. sodium potassium tartrate and extracted with EtOAc(2×). The combined organic layers were dried and concentrated. Theresulting residue was purified via SiO₂ chromatography (40-60%EtOAc/hexanes) to give 0.330 g (62%) of the title compound. MS (ESI):exact mass calcd. for C₁₉H₁₇FN₂O, 308.13; m/z found, 309.4 [M+H]⁺. ¹HNMR (CDCl₃): 8.77 (s, 1H), 7.58 (d, J=8.0, 2H), 7.38-7.35 (m, 2H), 7.29(d, J=7.9, 2H), 6.99-6.96 (m, 2H), 4.70 (s, 2H), 4.29 (s, 2H), 2.42 (s,3H).

Step C. The title compound was prepared using the methods described inExample 112, Step C. MS (ESI): exact mass calcd. for C₂₁H₂₂FN₃, 335.18;m/z found, 336.4 [M+H]⁺. ¹H NMR (CDCl₃): 8.67 (s, 1H), 7.69 (d, J=8.1,2H), 7.40-7.36 (m, 2H), 7.29 (d, J=7.9, 2H), 7.01-6.96 (m, 2H), 4.29 (s,2H), 3.36 (s, 2H), 2.42 (s, 3H), 2.22 (s, 6H).

Example 1174-(4-Fluoro-phenyl)-2-phenyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

The title compound was prepared as described in the preceding examples.MS (ESI): exact mass calcd. for C₁₉H₁₆FN₃, 305.35; m/z found, 306.4[M+H]⁺. ¹H NMR (CDCl₃): 8.48-8.46 (m, 2H), 7.66 (dd, J=5.4, 8.7, 2H),7.49-7.45 (m, 3H), 7.21-7.17, (m, J=8.7, 2H), 4.06 (s, 2H), 3.31 (t,J=6.1, 2H), 3.08 (t, J=6.1, 2H).

The following Examples 118-163 may be prepared according to the methodsdescribed in the preceding examples.

Example 1182-(3,3-Difluoro-cyclopentyl)-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine.

Example 1194-(4-Fluoro-phenyl)-2-(tetrahydro-furan-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

Example 1204-(4-Fluoro-phenyl)-2-(2-piperidin-1-yl-ethyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

Example 1212-(1-Fluoro-1-methyl-ethyl)-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

Example 1223-(4-Fluoro-phenyl)-5-isopropyl-4,6,12-triaza-tricyclo[7.2.1.0^(2,7)]dodeca-2,4,6-triene

Example 1237-(4-Fluoro-phenyl)-5-isopropyl-4,6,13-triaza-tricyclo[8.2.1.0^(3,8)]trideca-3,5,7-triene

Example 1244-(4-Fluoro-phenyl)-2-(tetrahydro-pyran-4-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

Example 1254-(4-Fluoro-phenyl)-2-(tetrahydro-pyran-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

Example 1264-(4-Fluoro-phenyl)-2-(2-methoxy-ethyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

Example 1272-[4-(4-Fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl]-propan-2-ol

Example 1284-(4-Fluoro-phenyl)-2-(1-methyl-1-phenyl-ethyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

Example 1292-Cyclopent-3-enyl-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

Example 1303-[4-(4-Fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl]-cyclohexanol

Example 1314-(4-Fluoro-phenyl)-2-piperidin-4-yl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

Example 1324-(4-Fluoro-phenyl)-2-(1-methyl-piperidin-4-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

Example 133[4-(4-Fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl]-phenyl-methanol

Example 1344-(4-Fluoro-phenyl)-2-(fluoro-phenyl-methyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

Example 1352-(Difluoro-phenyl-methyl)-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

Example 1364-(4-Fluoro-phenyl)-2-phenyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

Example 1374-(4-Fluoro-phenyl)-2-(3-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

Example 1384-(4-Fluoro-phenyl)-2-(4-methoxy-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

Example 1394-(4-Fluoro-phenyl)-2-o-tolyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

Example 1403-[4-(4-Fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl]-benzonitrile

Example 1414-(4-Fluoro-phenyl)-2-(2,2,2-trifluoro-1-trifluoromethyl-ethyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

Example 1424-(4-Fluoro-phenyl)-2-(1-methyl-cyclopropyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

Example 1432-[4-(4-Fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl]-2-methyl-propionicacid

Example 1442-[4-(4-Fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl]-propionicacid

Example 1452-(4-Fluoro-cyclohexyl)-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

Example 1462-(4,4-Difluoro-cyclohexyl)-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

Example 1474-(4-Fluoro-phenyl)-2-phenethyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

Example 1484-Furan-2-yl-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

Example 1492-Isopropyl-4-(5-methyl-furan-2-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

Example 1504-Furan-3-yl-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

Example 1514-(5-Fluoro-pyridin-2-yl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

Example 1522-Isopropyl-4-oxazol-2-yl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

Example 1534-(4,5-Dimethyl-oxazol-2-yl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

Example 1542-Isopropyl-4-thiazol-2-yl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

Example 1552-Isopropyl-4-(3H-[1,2,3]triazol-4-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

Example 1562-Isopropyl-4-(2H-pyrazol-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

Example 1572-Isopropyl-4-(1H-pyrazol-4-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

Example 1584-(4-Fluoro-phenyl)-2,6-diisopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

Example 1596-Ethyl-4-(4-fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

Example 1606-Cyclopropyl-4-(4-fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

Example 1616-Cyclobutyl-4-(4-fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

Example 1626-Cyclopentyl-4-(4-fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

Example 1636-Butyl-4-(4-fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidineExample 164 Alternative preparation of4-(4-fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

Step A.1-(3,4,5,6,3′,6′-Hexahydro-2H,2′H-[1,4′]bipyridinyl-1′-yl)-ethanone. Aflask equipped with a Dean-Stark trap and a reflux condenser was chargedwith 1-acetyl-piperdin-4-one (100 g, 0.71 mol) and toluene (1 L).Piperidine (63.4 g, 0.75 mol) and p-toluenesulfonic acid monohydrate(0.27 g, 1.4 mmol, 0.2 mol %) were added, and the resulting solution washeated at reflux for 8 h. The mixture was cooled to rt and concentratedto give a crude product which was used directly in the next reaction.

Step B.1-[5′-(4-Fluoro-benzoyl)-3,4,5,6,3′,6′-hexahydro-2H,2′H-[1,4′]bipyridinyl-1′-yl]-ethanone.A solution of crude1-(3,4,5,6,3′,6′-hexahydro-2H,2′H-[1,4′]bipyridinyl-1′-yl)-ethanone inCH₂Cl₂ (1.5 L) was treated with Et₃N (108 mL, 0.78 mol) and then cooledto 0° C. A solution of 4-fluorobenzoyl chloride (107 g, 0.68 mol) inCH₂Cl₂ (150 mL) was added over 1 h. The reaction mixture was stirred atrt for 2 h, then was concentrated to give a crude material which wasdirectly used on next reaction. HPLC: R_(T)=7.52 min. MS (ESI): exactmass calcd. for C₁₉H₂₃FN₂O₂, 330.17; m/z found, 331.0 [M+H]⁺.

Step C.1-[4-(4-Fluoro-phenyl)-2-isopropyl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl]-ethanone.A solution of crude1-[5′-(4-fluoro-benzoyl)-3,4,5,6,3′,6′-hexahydro-2H,2′H-[1,4′]bipyridinyl-1′-yl]-ethanonein t-amyl alcohol (1.5 L) was treated with Et₃N (108 mL, 0.78 mol) and2-methyl propanimidamide hydrochloride (82.6 g, 0.67 mol). The reactionmixture was heated at reflux for 16 h and then was cooled to rt. Themixture was concentrated, and the residue was diluted with water (2 L)and extracted with EtOAc (2×). The combined organic layers were dried(MgSO₄) and concentrated to afford the crude title compound, which wasused in next reaction without further purification. HPLC: R_(T)=8.11min. MS (ESI): exact mass calcd. for C₁₈H₂₀FN₃O, 313.16; m/z found,314.0 [M+H]⁺. ¹H NMR (CDCl₃; mixture of rotamers): 7.60-7.50 (m, 2H),7.24-7.12 (m, 2H), 4.71 (s, 1.4H), 4.56 (s, 0.6H), 3.93 (t, J=6.2,0.6H), 3.80 (t, J=6.2, 1.4H), 3.18 (sept, J=6.8, 1H), 3.07 (t, J=6.2,1.4H), 3.02 (t, J=6.2, 0.6H), 2.15 (s, 2.1H), 2.00 (s, 0.9H), 1.34 (d,J=6.8, 6H).

Step D. A mixture of crude1-[4-(4-fluoro-phenyl)-2-isopropyl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl]-ethanonein 10% aq. HCl (800 mL) was heated at reflux for 2 h and then cooled tort. The aqueous solution was washed with EtOAc (400 mL) and then wasbasified with NaOH pellets (˜120 g) to pH>12. The basic solution wasextracted with CH₂Cl₂ (2×500 mL). The combined organic layers werewashed with 1 N NaOH (400 mL), dried (MgSO₄), and concentrated to givethe crude product (100 g), which was used in the next reaction withoutfurther purification. HPLC: RT=6.89 min. MS (ESI): exact mass calcd. forC₁₆H₁₈FN₃, 271.15; m/z found, 271.9 [M+H]⁺.

Example 1654-(4-Fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine,citrate salt

A solution of crude4-(4-fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine(Example 164) in EtOH (1 L) was treated with citric acid (71 g, 0.37mol). The solution was warmed to 50° C. to form a homogeneous solution,then was cooled to rt and stirred for 16 h. The mixture was diluted withEt₂O (750 mL) and was stirred for 1 h. The precipitated white solid wascollected by filtration and washed with cold EtOH (ca. 100 mL). Thewhite solid was dried in a vacuum oven at 55° C. to give an off-whitesolid (157.3 g, 50% overall yield). HPLC: RT=6.86 min. MS (ESI): exactmass calcd. for C₁₆H₁₈FN₃, 271.15; m/z found, 271.9 [M+H]⁺. ¹H NMR(D₂O): 7.49-7.43 (m, 2H), 7.27-7.19 (m, 2H), 4.28 (s, 2H), 3.60 (t,J=6.5, 2H), 3.20 (t, J=6.5, 2H), 3.11 (sept, J=6.9, 1H), 2.77 (d,J=15.4, 2H), 2.65 (d, J=15.4, 2H), 1.23 (d, J=6.9, 6H). ¹³C NMR (D₂O):176.59, 172.69, 171.99, 162.59 (d, J_(C-F)=11.6), 160.67, 159.41,129.42, 128.53 (d, J_(C-F)=8.8), 115.91, 113.89 (d, J_(C-F)=22.4),71.78, 41,61, 40.10, 38.77, 34.78, 25.33, 18.64.

The compounds in Examples 166-167 were prepared using methods analogousto those described in the preceding examples.

Example 166{2-[2-tert-Butyl-6-(4-fluoro-phenyl)-pyrimidin-4-yl]-ethyl}-methyl-amine

MS (ESI): exact mass calcd. for C₁₇H₂₂FN₃, 287.18; m/z found, 288.7[M+H]⁺.

Example 167{2-[2-tert-Butyl-6-(4-fluoro-phenyl)-pyrimidin-4-yl]-ethyl}-dimethyl-amine

MS (ESI): exact mass calcd. for C₁₈H₂₄FN₃, 301.20; m/z found, 302.7[M+H]⁺.

Assay Methods

In Vitro Pharmacology

Stock drug solutions (10 mM) were prepared in DMSO (the final assayconcentration of DMSO not exceeding 0.4%). Drug dilutions were preparedin assay buffer.

Sigmoidal inhibition curves were generated and fitted by nonlinearregression analysis (GraphPad Prism). K_(i) values were calculatedaccording to the Cheng and Prussoff equation (Biochem. Pharmacol. 1973,22, 3099-3108), IC₅₀/(1+[S]/K_(d)), where the following values wereused: 5-HT₇ ([S]=1 nM; K_(d)=0.42); 5-HT_(2A) ([S]=1 nM; K_(d)=0.4 nM);5-HT_(2B) ([S]=4 nM; K_(d)=3.5 nM); 5-HT_(2C) ([S]=3 nM; K_(d)=3 nM);5HT₆ ([S]=1.7 nM; K_(d)=1.7 nM).

Data obtained for compounds tested in Assays 1-4 are presented in Table1 below.

1. Affinity for 5-HT₇ Receptor Binding Sites

The affinity of the compounds described in this invention for the 5-HT₇receptor binding site was evaluated by single competition radioligandbinding assay. The assay was performed on membranes prepared fromHEK-293 cells that had been subjected to stable transfection with therat 5-HT_(7a) receptor (GB: NM022938). Cells were scraped from theculture plates, suspended in Tris-HCl 50 mM pH 7.5 and collected throughcentrifugation (1000 rpm for 5 min). The cell pellets were homogenized(Polytron, 15 s, setting 5) in 50 mM Tris-HCl (pH 7.5), 5 mM EDTA.Following centrifugation (15,000 rpm for 25 min), membranes (135 μgprotein/mL) were resuspended in the same buffer and incubated for 60 minat RT with 1 nM [³H]5-CT in the presence of increasing concentration oftest compounds. Nonspecific binding was defined in the presence of 10 μM5-HT. Incubation was stopped by rapid filtration using the cellharvester (Packard). Radioactivity was counted in a TopCount-NXT(Packard). Experiments were conducted in triplicate.

2. Affinity for 5-HT2A Receptor Binding Sites

The affinity of the compounds for the rat 5-HT_(2A) receptor wasevaluated by competitive radioligand binding assay using [³H]ketanserineas the radioligand. The assay was performed on membranes from rat cortex(Schotte, A. et al. Psychopharmacology 1996, 124, 57-73). Brain tissue(rat cortex) was homogenized in 20 volumes per wet weight tissue ofTris-HCl buffer (50 mM, pH 7.4). The total membrane fraction wascollected by centrifugation and washed by subsequent centrifugation runs(25 min at 25,000 g at 4° C.). Membranes were re-suspended in Tris-HClbuffer (50 mM, pH 7.4) containing 1 nM [³H]ketanserin. Non-specificbinding was estimated in the presence of 10 μM risperidone. Theincubation was terminated by rapid filtration over Whatman GF/B filterspre-soaked in 0.1% polyethylenimine, and one washing step with 1 mLice-cold Tris-HCl buffer, pH 7.4.

3. Affinity for 5HT₂ Receptor Binding Sites

Receptor binding was performed using the human recombinant 5-HT_(2A)(GB: X57830), 5-HT_(2B) (GB: Z36748) and 5-HT_(2C) (GB: M81778)receptors. The affinity of the compounds for the 3 different human 5-HT₂receptor subtypes was evaluated by competitive radioligand bindingassays using [³H]ketanserin (h5-HT_(2A)) or [³H]mesulergine (h5-HT_(2B)and h5-HT_(2C)). The assays were performed on membranes prepared fromNIH3T3 stably transfected with h5-HT_(2A) or CHO stably transfected withh5-HT_(2B) and h5-HT_(2C).

4. Affinity for 5-HT₆ Receptor Binding Sites

Receptor binding was performed using the human recombinant 5-HT₆ (GB:BC0794995) receptor. The affinity of the compounds for the human 5-HT₆receptor was evaluated by competitive radioligand binding assays using[³H]LSD. The assays were performed on membranes prepared from HEK-293stably transfected with h5-HT₆. Non-specific binding was estimated inthe presence of 1 μM clozapine.

TABLE 1 Binding Affinities (nM) K_(i) K_(i) K_(i) K_(i) K_(i) Ex. 5-HT₇5-HT_(2A) 5-HT_(2B) 5-HT_(2C) 5-HT₆ 1 540 4 70 90 NT 2 >10000 20 5000510 NT 3 >10000 11 2250 1020 >10000 4 >10000 20 250 200 NT 5 >10000 13350 250 NT 6 >10000 50 200 300 NT 7 >10000 25 900 900 NT 8 1000 20 1000320 200 9 5000 1350 >10000 7500 NT 10 >10000 200 >10000 5000 NT11 >10000 100 >10000 2000 NT 12 >10000 300 >10000 5000 NT 13 >10000 12.52200 1000 NT 14 >10000 30 4000 4000 NT 15 >10000 1000 >10000 >10000 NT16 >10000 2000 >10000 >10000 NT 17 >10000 4 250 70 NT 18 525 10 80 60330 19 >10000 100 140 200 NT 20 >10000 700 1200 >10000 NT 21 >10000 251185 1170 >10000 22 >10000 32 500 1300 NT 23 >10000 500 >10000 >10000 NT24 >10000 240 >10000 >10000 NT 25 >10000 300 >10000 >10000 NT 26 >10000300 >10000 >10000 NT 27 >10000 60 >10000 >10000 NT 28 >10000 100 4003000 NT 29 >10000 240 1600 2000 >10000 30 >10000 800 1000 2500 NT31 >10000 70 2000 >10000 NT 32 >10000 2000 >10000 >10000 NT33 >10000 >10000 >10000 >10000 NT 34 >10000 150 400 1000 NT 35 500 70400 2000 NT 36 >10000 >10000 >10000 >10000 NT 37 >10000 40 400 1000 NT38 >10000 40 50 800 NT 39 >10000 150 >10000 >10000 NT 40 >10000500 >10000 >10000 NT 41 >10000 2000 5000 5000 NT 42 >10000120 >10000 >10000 NT 43 >10000 200 >10000 >10000 NT 44 >10000 400 5001000 NT 45 >10000 >10000 >10000 >10000 NT 46 120 14 30 200 100 47 30 2.51 22 12 48 40 20 3 100 24 49 300 50 25 400 200 50 240 3.7 20 80 26051 >10000 470 140 9000 NT 52 >10000 725 1150 9000 NT 53 >100001000 >10000 >10000 NT 54 5000 0.55 30 20 30 55 35 0.42 2.5 16 8.5 56 1800.80 22 38 30 57 550 0.70 40 50 80 58 >10000 2 40 30 100 59 100 1.5 7.829 20 60 400 6 10 60 60 61 250 1.9 15 35 20 62 5275 0.75 21 21 2763 >10000 1.5 52 46 60 64 >10000 10 1300 70 1300 65 >10000 20 300570 >10000 66 300 8 30 145 NT 67 5400 56 80 495 NT 68 >10000 80 660 7100NT 69 >10000 140 >10000 650 7100 70 >10000 117 >10000 3733 250 71 >100001027 4333 3583 300 72 >10000 130 >10000 >10000 NT 73 >10000140 >10000 >10000 NT 74 >10000 47 1900 >10000 NT 75 5000 70 3000 >10000NT 76 150 9 315 75 300 77 22 15 200 130 400 78 400 25 900 380 NT 79 300115 435 900 NT 80 >10000 11 158 940 2800 81 >10000 25 450 6000 NT82 >10000 2 500 20 230 83 >10000 30 1000 300 230 84 >10000 14 400 5000NT 85 >10000 82 1150 >10000 NT 86 9000 100 4100 >10000 NT 87 >10000 6002000 >10000 NT 88 550 13 60 185 NT 89 >10000 25 40 1400 NT 90 2300 17130 1000 NT 91 >10000 75 200 9000 NT 92 >10000 300 >10000 >10000 NT93 >10000 >10000 >10000 >10000 NT 94 >10000 >10000 >10000 >10000 NT95 >10000 2000 >10000 >10000 NT 96 >10000 >10000 >10000 >10000 NT97 >10000 >10000 >10000 >10000 NT 98 >10000 >10000 >10000 >10000 NT99 >10000 >10000 >10000 >10000 NT 100 >10000 14 900 300 NT 101 >10000400 >10000 >10000 NT 102 >10000 20 150 230 370 103 >10000 40 1000 1000NT 104 >10000 700 500 3000 NT 105 >10000 40 100 400 NT 106 >10000 906300 >10000 NT 107 >10000 12 275 500 4000 108 >10000 18 42 1000 NT109 >10000 400 >10000 >10000 >10000 110 >10000 220 1200 4000 NT111 >10000 300 3500 >10000 NT 112 >10000 130 >10000 >10000 NT 113 >10000650 >10000 >10000 NT 114 >10000 35 300 1000 NT 115 5000 1000 5000 >10000NT 116 >10000 2000 >10000 >10000 NT 117 >10000 50 1000 4000 NT 166 NT 1118 170 NT 167 450 7 14 200 NT NT = not tested

5. In Vitro Functional Assay for 5-HT₂ Receptor (Intracellular Calcium)

In vitro functional properties of these compounds on the different 5-HT₂receptor subtypes were determined using fluorometric imaging platereader (FLIPR) based calcium assay as previously described (Porter, R.H. et al. Br. J. Pharmacol. 1999, 128, 13-20; Jerman, J. C. et al. Eur.J. Pharmacol. 2001, 414, 23-30). The 5-HT₂ receptors are linked to theGq family of G proteins and to subsequent activation of phospholipase C,induction of phosphoinositide metabolism and to an increase inintracellular calcium concentration. The same cell lines as described inthe previous section (receptor binding) were used for the FLIPRexperiments. Data obtained for compounds tested are presented in Table2.

TABLE 2 pK_(b) pK_(b) pK_(b) Ex. 5-HT_(2A) 5-HT_(2B) 5-HT_(2C) 13 7.1 5NT 17 8.1 5.4 NT 18 7.6 6.7 NT 21 7.5 5 5 50 8.3 8.3 NT 57 8.2 6.9 NT 628.8 7.3 NT 63 7.8 6.3 NT 64 7.1 5 NT 69 6 5 NT 76 7 5 NT 78 7.1 5 NT 828.1 5.4 NT 100 7 5 NT NT = not tested

1. A compound of Formulae (I) or (II):

wherein m is 1, 2, or 3; n is 1, 2, or 3; where m and n are present, m+nis greater than or equal to 2, and is less than or equal to 4; R^(a) andR^(b) are independently —H, —C₁₋₇alkyl, or —C₃₋₇cycloalkyl, or R^(a) andR^(b) taken together with the nitrogen of attachment form piperidinyl,pyrrolidinyl, morpholinyl, thiomorpholinyl, or piperazinyl, where eachR^(a) and R^(b) is optionally and independently substituted with—C₁₋₄alkyl; q is 0 or 1; A is >NR¹, >CHNR^(c)R^(d), >CHOH, or —CH₂—,wherein R¹ is selected from the group consisting of —H, —C₁₋₇alkyl,—C₃₋₇cycloalkyl, and benzyl, where each alkyl, cycloalkyl, or benzyl isoptionally mono-, di-, or tri-substituted with R^(e); R^(e) is selectedfrom the group consisting of —C₁₋₄alkyl, —C₂₋₄alkenyl, -C₂₋₄alkynyl,—C₃₋₆cycloalkyl, halo, —CF₃, —OH, —OC₁₋₄alkyl, —OCF₃, —N(R^(f))R^(g)(wherein R^(f) and R^(g) are independently —H or —C₁₋₄alkyl, or R^(f)and R^(g) taken together with the nitrogen of attachment formpiperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, orpiperazinyl), —C(O)N(R^(f))R^(g), —N(R^(h))C(O)R^(h),—N(R^(h))SO₂C₁₋₇alkyl (wherein R^(h) is —H or —C₁₋₄alkyl, or two R^(h)in the same substituent taken together with the amide of attachment forman otherwise aliphatic 4- to 6-membered ring), —S(O)₀₋₂—C₁₋₄alkyl,—SO₂N(R^(f))R^(g), —SCF₃, —C(O)C₁₋₄alkyl, —CN, —COOH, and —COOC₁₋₄alkyl;R^(c) and R^(d) are independently selected from the group consisting of—H, —C₁₋₇alkyl, —C₃₋₇alkenyl, —C₃₋₇alkynyl, —C₃₋₇cycloalkyl,—C₁₋₇alkylC₃₋₇cycloalkyl, and —C₃₋₇cycloalkylC₁₋₇alkyl, or R^(c) andR^(d) taken together with the nitrogen of attachment form piperidinyl,pyrrolidinyl, morpholinyl, thiomorpholinyl, or piperazinyl, where eachR^(c) and R^(d) is optionally and independently substituted with R^(e);R³ is —C₁₋₄alkyl, —C₁₋₄alkenyl, or benzyl, each optionally substitutedwith —C₁₋₃alkyl, —OH, or halo, or two R³ substituents taken togetherform C₂₋₅alkylene optionally substituted with —C₁₋₃alkyl, —OH, or halo;r is 0 or is an integer less than or equal to m+n+1; Ar is an aryl orheteroaryl ring selected from the group consisting of: a) phenyl,optionally mono-, di-, or tri-substituted with R^(i) or di-substitutedon adjacent carbons with —OC₁₋₄alkyleneO—, —(CH₂)₂₋₃NH—,—(CH₂)₁₋₂NH(CH₂)—, —(CH₂)₂₋₃N(C₁₋₄alkyl)-, or—(CH₂)₁₋₂N(C₁₋₄alkyl)(CH₂)—; R^(i) is selected from the group consistingof —C₁₋₇alkyl, —C₂₋₇alkenyl, —C₂₋₇alkynyl, —C₃₋₇cycloalkyl, halo, —CF₃,—OH, —OC₁₋₇alkyl, —OCF₃, —OC₃₋₇alkenyl, —OC₃₋₇alkynyl, —N(R^(j))R^(k)(wherein R^(j) and R^(k) are independently —H or —C₁₋₄alkyl),—C(O)N(R^(j))R^(k), —N(R^(j))C(O)R^(k), —N(R^(j))SO₂C₁₋₆alkyl,—S(O)₀₋₂—C₁₋₆alkyl, —SO₂N(R^(j))R^(k), —SCF₃, —C(O)C₁₋₆alkyl, —NO₂, —CN,—COOH, and —COOC₁₋₇alkyl; b) a monocyclic aromatic hydrocarbon grouphaving five ring atoms, having a carbon atom which is the point ofattachment, having one carbon atom replaced by >O, >S, >NH, or>N(C₁₋₄alkyl), having up to two additional carbon atoms optionallyreplaced by —N═, optionally mono- or di-substituted with R^(i); c) amonocyclic aromatic hydrocarbon group having six ring atoms, having acarbon atom which is the point of attachment, having one or two carbonatoms replaced by —N═, optionally mono- or di-substituted with R^(i);and d) phenyl or pyridyl, substituted with a substituent selected fromthe group consisting of phenyl, phenoxy, pyridyl, thiophenyl, oxazolyl,and tetrazolyl, where the resultant substituted moiety is optionallyfurther mono-, di-, or tri-substituted with R^(i); ALK is a branched orunbranched C₁₋₇alkylene, C₂₋₇alkenylene, C₂₋₇alkynylene,C₃₋₇cycloalkylene, or C₃₋₇cycloalkenylene, optionally mono-, di-, ortri-substituted with R^(m); R^(m) is selected from the group consistingof halo, —CF₃, —OH, —OC₁₋₇alkyl, —OC₃₋₇cycloalkyl, —OCF₃, —N(R^(p))R^(s)(wherein R^(p) and R^(s) are independently —H or —C₁₋₇alkyl),—C(O)N(R^(p))R^(s), —N(R^(t))C(O)R^(t), —N(R^(t))SO₂C₁₋₆alkyl (whereinR^(t) is —H or —C₁₋₇alkyl), —S(O)₀₋₂—C₁₋₆alkyl, —SO₂N(R^(p))R^(s),—SCF₃, —CN, —NO₂, —C(O)C₁₋₇alkyl, —COOH, and —COOC₁₋₇alkyl; CYC is —H oris a ring system selected from the group consisting of: i) phenyl,optionally mono-, di-, or tri-substituted with R^(u) or di-substitutedon adjacent carbons with —OC₁₋₄alkyleneO—, —(CH₂)₂₋₃NH—,—(CH₂)₁₋₂NH(CH₂)—, —(CH₂)₂₋₃N(C₁₋₄alkyl)-, or—(CH₂)₁₋₂N(C₁₋₄alkyl)(CH₂)—; R^(u) is selected from the group consistingof —C₁₋₇alkyl, —C₃₋₇cycloalkyl, phenyl, benzyl, halo, —CF₃, —OH,—OC₁₋₇alkyl, —OC₃₋₇cycloalkyl, —Ophenyl, —Obenzyl, —OCF₃, —N(R^(v))R^(w)(wherein R^(v) and R^(w) are independently —H or —C₁₋₇alkyl, or R^(v)and R^(w) taken together with the nitrogen of attachment formpiperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, or piperazinyl,where each R^(v) and R^(w) is optionally and independently substitutedwith —OH or —C₁₋₇alkyl), —C(O)N(R^(v))R^(w), —N(R^(x))C(O)R^(x),—N(R^(x))SO₂C₁₋₆alkyl (wherein R^(x) is —H or —C₁₋₇alkyl, or two R^(x)in the same substituent taken together with the amide of attachment forman otherwise aliphatic 4- to 6-membered ring), —N—(SO₂C₁₋₆alkyl)₂,—S(O)₀₋₂—C₁₋₆alkyl, —SO₂N(R^(v))R^(w), —SCF₃, —C(O)C₁₋₆alkyl, —NO₂, —CN,—COOH, and —COOC₁₋₇alkyl; ii) a monocyclic aromatic hydrocarbon grouphaving five ring atoms, having a carbon atom which is the point ofattachment, having one carbon atom replaced by >O, >S, >NH, or>N(C₁₋₄alkyl), having up to one additional carbon atoms optionallyreplaced by —N═, optionally mono- or di-substituted with R^(u); iii) amonocyclic aromatic hydrocarbon group having six ring atoms, having acarbon atom which is the point of attachment, having one or two carbonatoms replaced by —N═, optionally mono- or di-substituted with R^(u);and iv) a non-aromatic heterocyclic ring having 4 to 8 members, saidring having 0, 1, or 2 non-adjacent heteroatom members selected from thegroup consisting of O, S, —N═, >NH, and >N(C₁₋₄alkyl), having 0, 1, or 2double bonds, having 0, 1, or 2 carbon members which is a carbonyl,optionally having one carbon member which forms a bridge, having 0 to 5substituents R^(u), and where when q is 0, said ring has a carbon atomwhich is the point of attachment; and enantiomers, diastereomers,hydrates, solvates and pharmaceutically acceptable salts, esters andamides thereof; with the proviso that in Formula (I): (a) when ALK ismethylene, ethylene, propylene, or isopropylene, CYC is —H, Ar is phenylor mono-substituted phenyl, m is 2, n is 1, and A is >NR¹, then R¹ isnot —C₁₋₄alkyl or benzyl; (b) when q is 0, CYC is phenyl, Ar is phenylor 3-chlorophenyl, m is 2, and n is 1, then A is not unsubstituted—CH₂—; and (c) when q is 0, CYC is 2-pyridyl, Ar is 2-pyridyl, m is 2,and n is 1, then A is not unsubstituted —CH₂—.
 2. The compound of claim1 wherein m is 1 and n is
 1. 3. The compound of claim 1 wherein m is 1and n is
 2. 4. The compound of claim 1 wherein m is 2 and n is
 1. 5. Thecompound of claim 1 wherein m is 2 and n is
 2. 6. The compound of claim1 wherein m is 1 and n is
 3. 7. The compound of claim 1 wherein m is 3and n is
 1. 8. The compound of claim 1 wherein n is 1 in Formula (II).9. The compound of claim 1 wherein n is 2 in Formula (II).
 10. Thecompound of claim 1 wherein q is
 1. 11. The compound of claim 1 wherein—N(R^(a))R^(b) is amino, methylamino, ethylamino, isopropylamino,dimethylamino, diethylamino, diisopropylamino, cyclopropylamino,cyclopentylamino, piperidinyl, pyrrolidinyl, morpholinyl,thiomorpholinyl, or piperazinyl.
 12. The compound of claim 1 wherein—N(R^(a))R^(b) is amino, methylamino, dimethylamino, orN-methylpiperazinyl.
 13. The compound of claim 1 wherein A is >NR¹. 14.The compound of claim 1 wherein R¹ is selected from the group consistingof hydrogen, methyl, ethyl, isopropyl, butyl, hexyl, cyclopropyl,cyclobutyl, cyclopentyl, and benzyl, each optionally mono-, di-, ortri-substituted with R^(e).
 15. The compound of claim 1 wherein R¹,optionally R^(e) substituted, is selected from the group consisting ofhydrogen, methyl, ethyl, isopropyl, and benzyl.
 16. The compound ofclaim 1 wherein R¹ is hydrogen or methyl.
 17. The compound of claim 1wherein R³, optionally substituted, is selected from the groupconsisting of methyl, ethyl, propyl, isopropyl, butyl, methylene, allyl,and benzyl.
 18. The compound of claim 1 wherein two R³ substituentstaken together form ethylene.
 19. The compound of claim 1 wherein R³ ismethyl.
 20. The compound of claim 1 wherein r is 0, 1, or
 2. 21. Thecompound of claim 1 wherein Ar, optionally substituted, is selected fromthe group consisting of: a) phenyl, 5-,6-,7-,8-benzo-1,4-dioxanyl,4-,5-,6-,7-benzo-1,3-dioxolyl, 4-,5-,6-,7-indolinyl,4-,5-,6-,7-isoindolinyl, 1,2,3,4-tetrahydro-quinolin-4,5,6 or 7-yl,1,2,3,4-tetrahydro-isoquinolin-4,5,6 or 7-yl, b) furanyl, oxazolyl,isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, thiophenyl, thiazolyl, isothiazolyl, pyrrolyl,imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, c) pyridinyl,pyridinyl-N-oxide, pyrazinyl, pyrimidinyl, pyridazinyl, and d) biphenyl,and 4-tetrazolylphenyl.
 22. The compound of claim 1 wherein Ar,optionally substituted, is selected from the group consisting of phenyl,pyridyl, thiophen-2-yl, and thiophen-3-yl.
 23. The compound of claim 1wherein Ar is selected from the group consisting of phenyl,2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-methylphenyl,3-methylphenyl, 4-methylphenyl, 4-ethylphenyl, 2-chlorophenyl,3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl,4-fluorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl,2-trifluoromethylphenyl, 3-trifluoromethylphenyl,4-trifluoromethylphenyl, 3-trifluoromethoxyphenyl,4-trifluoromethoxyphenyl, 3-cyanophenyl, 4-cyanophenyl, 3-acetylphenyl,4-acetylphenyl, 3,4-difluorophenyl, 3,4-dichlorophenyl,2,3-difluorophenyl, 2,3-dichlorophenyl, 2,4-difluorophenyl,2,4-dichlorophenyl, 3-nitrophenyl, 4-nitrophenyl,3-chloro-4-fluorophenyl, 3-fluoro-4-chlorophenyl, benzo[1,3]dioxol-4 or5-yl, 3-hydroxyphenyl, 4-hydroxyphenyl, 4-hydroxy-2-methylphenyl,4-hydroxy-3-fluorophenyl, 3,4-dihydroxyphenyl,4-dimethylaminophenyl,4-carbamoylphenyl, 4-fluoro-3-methylphenyl, 2-phenoxyphenyl, furan-2-yl,furan-3-yl, 5-methyl-furan-2-yl, thiophen-2-yl, thiophen-3-yl,5-chlorothiophen-2-yl, 5-methylthiophen-2-yl, 5-chlorothiophen-3-yl,5-methylthiophen-3-yl, oxazol-2-yl, 4,5-dimethyl-oxazol-2-yl,thiazol-2-yl, 3H-[1,2,3]triazol-4-yl, 2H-pyrazol-3-yl, 1H-pyrazol-4-yl,4-pyridyl, 5-fluoro-pyridin-2-yl, 4′-chlorobiphenyl, and4-tetrazolylphenyl.
 24. The compound of claim 1 wherein ALK, optionallysubstituted, is selected from the group consisting of methylene,ethylene, propylene, butylene, sec-butylene, tert-butylene, pentylene,1-ethylpropylene, 2-ethylpropylene, 2-ethylbutylene, isopropylene,but-3-enylene, isobutylene, 3-methylbutylene, allylene, prop-2-ynylene,cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, andcycloheptylene.
 25. The compound of claim 1 wherein ALK is selected fromthe group consisting of methylene, hydroxymethylene, fluoromethylene,difluoromethylene, trifluoromethylmethylene,2,2,2-trifluoro-1-trifluoromethyl-ethylene, methoxycarbonylmethyl,methylcarbamoylmethyl, ethylene, 2-dimethylaminoethylene,2-cyanoethylene, 2-methoxyethylene, 1-carboxy-ethylene, propylene,3-methoxycarbonyl propylene, 3-carboxy propylene, isopropylene,1-fluoro-1-methyl-ethylene, 1-hydroxy-1-methyl-ethylene,1-carboxy-1-methyl-ethylene, 1-ethylpropylene, 2-ethylpropylene,butylene, tert-butylene, sec-butylene, isobutylene, 4-hydroxybutylene,4-methoxycarbonyl butylene, 4-carboxy butylene, 2-ethylbutylene,isobutylene, 3-methylbutylene, prop-2-ynylene, but-3-enylene, pentylene,5-hydroxypentylene, cyclopropylene, cyclobutylene, cyclopentylene,cyclopentenylene, 3,3-difluoro-cyclopentylene, 3-hydroxy-cyclohexylene,4-fluorocyclohexylene, 4,4-difluoro-cyclohexylene, and1-methyl-cyclopropylene.
 26. The compound of claim 1 wherein CYC,optionally substituted, is hydrogen or is a ring system selected fromthe group consisting of: i) phenyl, 5-,6-,7-,8-benzo-1,4-dioxanyl,4-,5-,6-,7-benzo-1,3-dioxolyl, 4-,5-,6-,7-indolinyl,4-,5-,6-,7-isoindolinyl, 1,2,3,4-tetrahydro-quinolin-4,5,6 or 7-yl,1,2,3,4-tetrahydro-isoquinolin-4,5,6 or 7-yl, ii) furanyl, oxazolyl,isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, thiophenyl, thiazolyl, isothiazolyl, pyrrolyl,imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, iii) pyridinyl,pyridinyl-N-oxide, pyrazinyl, pyrimidinyl, pyridazinyl, and iv)pyrrolinyl, pyrrolidinyl, pyrazolinyl, piperidinyl, homopiperidinyl,azepanyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl,morpholinyl, thiomorpholinyl, and piperidinonyl.
 27. The compound ofclaim 1 wherein CYC, optionally substituted, is selected from the groupconsisting of hydrogen, phenyl, thiophen-2-yl, thiophen-3-yl,furan-2-yl, furan-3-yl, pyridinyl, piperidin-1,2,3 or 4-yl,2-pyrrolin-2,3,4, or 5-yl, 3-pyrrolin-2 or 3-yl, 2-pyrazolin-3,4 or5-yl, tetrahydrofuran-3-yl, tetrahydropyran-4-yl, morpholin-2,3, or4-yl, thiomorpholin-2,3, or 4-yl, piperazin-1,2,3, or 4-yl,pyrrolidin-1,2, or 3-yl, and homopiperidinyl.
 28. The compound of claim1 wherein CYC, optionally substituted, is selected from the groupconsisting of hydrogen, phenyl, pyridyl, thiophen-2-yl, thiophen-3-yl,tetrahydropyranyl, furan-2-yl, furan-3-yl, tetrahydrofuran-3-yl, andpiperidinyl.
 29. The compound of claim 1 wherein CYC is selected fromthe group consisting of hydrogen, phenyl, 2-methoxyphenyl,3-methoxyphenyl, 4-methoxyphenyl, 2-methylphenyl, 3-methylphenyl,4-methylphenyl, 4-ethylphenyl, 2-chlorophenyl, 3-chlorophenyl,4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl,2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-trifluoromethylphenyl,3-trifluoromethylphenyl, 4-trifluoromethylphenyl,3-trifluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 2-cyanophenyl,3-cyanophenyl, 4-cyanophenyl, 3-acetylphenyl, 4-acetylphenyl,3,4-difluorophenyl, 3,4-dichlorophenyl, 2,3-difluorophenyl,2,3-dichlorophenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl,2,6-difluorophenyl, 2,6-dichlorophenyl, 2,6-dimethylphenyl,2,4,6-trifluorophenyl, 2,4,6-trichlorophenyl, 3,4,5-trimethoxyphenyl,4-fluoro-3-methylphenyl, 3-nitrophenyl, 4-nitrophenyl,4-methyl-3-fluorophenyl, 3,4-dimethylphenyl, 4-methoxy-3-fluorophenyl,4-methoxy-2-methylphenyl, 3-aminophenyl, 4-aminophenyl,4-carbomethoxyphenyl, 3-methanesulfonylamino-phenyl,4-methanesulfonylamino-phenyl, 3-dimethanesulfonylamino-phenyl,4-dimethanesulfonylamino-phenyl, thiophen-2-yl, thiophen-3-yl,5-chlorothiophen-2-yl, benzo[1,3]dioxol-4 or 5-yl, tetrahydrofuran-3-yl,tetrahydropyran-2,3 or 4-yl, furan-2-yl, furan-3-yl,5-carboxyethyl-furan-2-yl, piperidinyl, 3,4-bisbenzyloxyphenyl,2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl,4-hydroxy-2-methylphenyl, 4-hydroxy-3-fluorophenyl, 3,4-dihydroxyphenyl,1-piperidinyl, 4-piperidinyl, and 1-methyl-4-piperidinyl.
 30. A compoundselected from the group consisting of:2-tert-Butyl-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;2-Benzyl-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;2-sec-Butyl-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidinehydrochloride;2-sec-Butyl-4-p-tolyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidinehydrochloride;2-Cyclobutyl-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidinehydrochloride;2-Cyclobutyl-4-p-tolyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;2-Cyclopropyl-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;2-Benzyl-4-p-tolyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;2-Benzyl-4-(4-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;2-Benzyl-4-(3,4-difluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;2-Benzyl-4-phenyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;2-Benzyl-4-(3-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;2-(4-Fluoro-benzyl)-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;2-(4-Fluoro-benzyl)-4-(4-fluoro-phenyl)-6-methyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;4-[2-(4-Fluoro-benzyl)-6-methyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yl]-benzonitrile;4-[2-(4-Fluoro-benzyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yl]-benzonitrile;2-Cyclopentyl-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;2-Cyclopentyl-4-p-tolyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;2-Cyclopentyl-4-(4-methoxy-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;4-(2-Cyclopentyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yl)-benzonitrile;4-(4-Fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidinehydrochloride;4-(4-Fluoro-phenyl)-2-isopropyl-6-methyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;4-(3,4-Dichloro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidinehydrochloride;4-(3,4-Difluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidinehydrochloride;4-(3-Fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;4-(2-Fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;4-(2,4-Difluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;2-Isopropyl-4-p-tolyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;4-(4-Chloro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;2-Isopropyl-4-(4-methoxy-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;2-Isopropyl-4-phenyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;2-Isopropyl-4-(4-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;2-Isopropyl-4-(2-phenoxy-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;2-Isobutyl-4-thiophen-3-yl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;2-Isobutyl-4-thiophen-2-yl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;2-Isobutyl-4-pyridin-4-yl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;4-(4-Fluoro-phenyl)-2-isobutyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;2-Isobutyl-4-p-tolyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;4-(4-Fluoro-3-methyl-phenyl)-2-isobutyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;4-(2-Isobutyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yl)-benzonitrile;2-Isobutyl-4-(4-methoxy-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;2-sec-Butyl-4-(2-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidinehydrochloride;2-sec-Butyl-4-(3-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;2-sec-Butyl-4-(4-methoxy-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;2-sec-Butyl-4-(4-trifluoromethoxy-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;2-Cyclopentyl-4-(4-fluoro-phenyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine;2-Cyclopentyl-4-p-tolyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine;2-Cyclopentyl-4-(4-methoxy-phenyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine;4-(2-Cyclopentyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl)-benzonitrile;4-(4-Fluoro-phenyl)-2-isopropyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepinehydrochloride;4-(4-Chloro-phenyl)-2-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine;2-Methyl-4-phenyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine;4-(3-Chloro-phenyl)-2-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine;2-Benzyl-4-(4-fluoro-phenyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine;2-Benzyl-4-p-tolyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine;2-Benzyl-4-(4-trifluoromethyl-phenyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine;2-(4-Fluoro-benzyl)-4-(4-fluoro-phenyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine;2-Cyclopentyl-4-(4-fluoro-phenyl)-7-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine;2-Cyclopentyl-7-methyl-4-p-tolyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine;2-Cyclopentyl-4-(4-methoxy-phenyl)-7-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine;2-Benzyl-7-methyl-4-p-tolyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine;2-(4-Fluoro-benzyl)-4-(4-fluoro-phenyl)-7-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine;2-(4-Fluoro-benzyl)-4-(4-fluoro-phenyl)-7-methyl-9-methylene-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine;2-Benzyl-4-(4-fluoro-phenyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepinehydrochloride;4-(4-Fluoro-phenyl)-2-isopropyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepinehydrochloride;2-Isopropyl-4-p-tolyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepinehydrochloride;2-Isopropyl-4-(4-methoxy-phenyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepine;2-Isopropyl-4-phenyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepine;2-Benzyl-4-(4-fluoro-phenyl)-6,7,8,9-tetrahydro-5H-1,3,6-triaza-benzocycloheptenehydrochloride;2,7-Dibenzyl-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidinehydrochloride;2,7-Dibenzyl-4-p-tolyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine;2,7-Dibenzyl-4-phenyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine;2,7-Dibenzyl-4-(4-methoxy-phenyl)-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine;7-Benzyl-4-(4-fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine;7-Benzyl-2-isopropyl-4-phenyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine;2-Benzyl-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidinehydrochloride;2-Benzyl-4-p-tolyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidinehydrochloride;2-Benzyl-4-phenyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine;2-Benzyl-4-(4-methoxy-phenyl)-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine;4-(4-Fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidinehydrochloride;2-Isopropyl-4-phenyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine;2-Benzyl-4-(4-fluoro-phenyl)-7-methyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidinehydrochloride;2-Benzyl-4-(4-fluoro-phenyl)-7-isopropyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine;4-(4-Fluoro-phenyl)-2-isopropyl-7-methyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidinehydrochloride;2-Isopropyl-7-methyl-4-phenyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine;7-Benzyl-2-isopropyl-4-(5-methyl-thiophen-3-yl)-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidinehydrochloride;7-Benzyl-2-isopropyl-4-thiophen-3-yl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidinehydrochloride;2-Isopropyl-4-(5-methyl-thiophen-3-yl)-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidinehydrochloride;2-Isopropyl-4-thiophen-3-yl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidinehydrochloride;2-Isopropyl-7-methyl-4-(5-methyl-thiophen-3-yl)-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidinehydrochloride;2-Isopropyl-7-methyl-4-thiophen-3-yl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidinehydrochloride;6-Benzyl-4-(4-fluoro-phenyl)-2-isopropyl-8-methyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;6-Benzyl-4-(3-chloro-4-fluoro-phenyl)-2-isopropyl-8-methyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;6-Benzyl-2-isopropyl-8-methyl-4-p-tolyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;6-Benzyl-2-isopropyl-8-methyl-4-phenyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;6-Benzyl-2-isopropyl-8-methyl-4-(4-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;6-Benzyl-4-(4-chloro-phenyl)-2-isopropyl-8-methyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;6-Benzyl-2-isopropyl-8-methyl-4-thiophen-3-yl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;6-Benzyl-4-(4′-chloro-biphenyl-4-yl)-2-isopropyl-8-methyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;4-(4-Fluoro-phenyl)-2-isopropyl-8-methyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidinehydrochloride;4-(3-Chloro-4-fluoro-phenyl)-2-isopropyl-8-methyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidinehydrochloride;2-Isopropyl-8-methyl-4-p-tolyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidinehydrochloride;2-Isopropyl-8-methyl-4-phenyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;2-Isopropyl-8-methyl-4-(4-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;2-Isopropyl-8-methyl-4-thiophen-3-yl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;4-(4-Fluoro-phenyl)-2-isopropyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidinehydrochloride;4-(4-Fluoro-phenyl)-2-isopropyl-7-pyrrolidin-1-yl-5,6,7,8-tetrahydro-quinazoline;[4-(4-Fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-quinazolin-7-yl]-methyl-aminehydrochloride;[4-(4-Fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-quinazolin-6-yl]-methyl-aminehydrochloride;4-(4-Fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-quinazolin-7-ol;4-(4-Fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-quinazoline;(2-Benzyl-6-p-tolyl-pyrimidin-4-ylmethyl)-dimethyl-amine;2-Benzyl-4-(4-methyl-piperazin-1-ylmethyl)-6-p-tolyl-pyrimidine;[6-(4-Fluoro-phenyl)-2-isopropyl-pyrimidin-4-ylmethyl]-methyl-amine;2-(2-Benzyl-6-p-tolyl-pyrimidin-4-yl)-ethylamine;[2-(4-Fluoro-benzyl)-4-p-tolyl-pyrimidin-5-ylmethyl]-dimethyl-amine;4-(4-Fluoro-phenyl)-2-phenyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;2-(3,3-Difluoro-cyclopentyl)-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;4-(4-Fluoro-phenyl)-2-(tetrahydro-furan-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;4-(4-Fluoro-phenyl)-2-(2-piperidin-1-yl-ethyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;2-(1-Fluoro-1-methyl-ethyl)-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;3-(4-Fluoro-phenyl)-5-isopropyl-4,6,12-triaza-tricyclo[7.2.1.0^(2,7)]dodeca-2,4,6-triene;7-(4-Fluoro-phenyl)-5-isopropyl-4,6,13-triaza-tricyclo[8.2.1.0^(3,8)]trideca-3,5,7-triene;4-(4-Fluoro-phenyl)-2-(tetrahydro-pyran-4-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;4-(4-Fluoro-phenyl)-2-(tetrahydro-pyran-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;4-(4-Fluoro-phenyl)-2-(2-methoxy-ethyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;2-[4-(4-Fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl]-propan-2-ol;4-(4-Fluoro-phenyl)-2-(1-methyl-1-phenyl-ethyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;2-Cyclopent-3-enyl-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;3-[4-(4-Fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl]-cyclohexanol;4-(4-Fluoro-phenyl)-2-piperidin-4-yl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;4-(4-Fluoro-phenyl)-2-(1-methyl-piperidin-4-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;[4-(4-Fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl]-phenyl-methanol;4-(4-Fluoro-phenyl)-2-(fluoro-phenyl-methyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;2-(Difluoro-phenyl-methyl)-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;4-(4-Fluoro-phenyl)-2-phenyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;4-(4-Fluoro-phenyl)-2-(3-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;4-(4-Fluoro-phenyl)-2-(4-methoxy-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;4-(4-Fluoro-phenyl)-2-o-tolyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;3-[4-(4-Fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl]-benzonitrile;4-(4-Fluoro-phenyl)-2-(2,2,2-trifluoro-1-trifluoromethyl-ethyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;4-(4-Fluoro-phenyl)-2-(1-methyl-cyclopropyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;2-[4-(4-Fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl]-2-methyl-propionicacid;2-[4-(4-Fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl]-propionicacid;2-(4-Fluoro-cyclohexyl)-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;2-(4,4-Difluoro-cyclohexyl)-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;4-(4-Fluoro-phenyl)-2-phenethyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;4-Furan-2-yl-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;2-Isopropyl-4-(5-methyl-furan-2-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;4-Furan-3-yl-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;4-(5-Fluoro-pyridin-2-yl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;2-Isopropyl-4-oxazol-2-yl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;4-(4,5-Dimethyl-oxazol-2-yl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;2-Isopropyl-4-thiazol-2-yl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;2-Isopropyl-4-(3H-[1,2,3]triazol-4-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;2-Isopropyl-4-(2H-pyrazol-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;2-Isopropyl-4-(1H-pyrazol-4-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;4-(4-Fluoro-phenyl)-2,6-diisopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;6-Ethyl-4-(4-fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;6-Cyclopropyl-4-(4-fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;6-Cyclobutyl-4-(4-fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;6-Cyclopentyl-4-(4-fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;6-Butyl-4-(4-fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;and4-(4-Fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine,citrate salt.
 31. The compound of claim 1 wherein said pharmaceuticallyacceptable salt is an effective amino addition salt.
 32. The compound ofclaim 1 wherein said pharmaceutically acceptable salt is selected fromthe group consisting of hydrobromide, hydrochloride, sulfate, bisulfate,nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate,laurate, borate, benzoate, lactate, phosphate, tosylate, citrate,maleate, fumarate, succinate, tartrate, naphthylate, mesylate,glucoheptonate, lactiobionate, and laurylsulfonate.
 33. A pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and atherapeutically effective amount of at least one compound of Formulae(I) or (II):

wherein m is 1, 2, or 3; n is 1, 2, or 3; where when m and n are bothpresent, m+n is greater than or equal to 2, and is less than or equal to4; R^(a) and R^(b) are independently —H, —C₁₋₇alkyl, or —C₃₋₇cycloalkyl,or R^(a) and R^(b) taken together with the nitrogen of attachment formpiperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, or piperazinyl,where each R^(a) and R^(b) is optionally and independently substitutedwith —C₁₋₄alkyl; q is 0 or 1; A is >NR¹, >CHNR^(c)R^(d), >CHOH, or—CH₂—, wherein R¹ is selected from the group consisting of —H,—C₁₋₇alkyl, —C₃₋₇cycloalkyl, and benzyl, where each alkyl, cycloalkyl,or benzyl is optionally mono-, di-, or tri-substituted with R^(e); R^(e)is selected from the group consisting of —C₁₋₄alkyl, —C₂₋₄alkenyl,—C₂₋₄alkynyl, —C₃₋₆cycloalkyl, halo, —CF₃, —OH, —OC₁₋₄alkyl, —OCF₃,—N(R^(f))R^(g) (wherein R^(f) and R^(g) are independently —H or—C₁₋₄alkyl, or R^(f) and R^(g) taken together with the nitrogen ofattachment form piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl,or piperazinyl), —C(O)N(R^(f))R^(g), —N(R^(h))C(O)R^(h),—N(R^(h))SO₂C₁₋₇alkyl (wherein R^(h) is —H or —C₁₋₄alkyl, or two R^(h)in the same substituent taken together with the amide of attachment forman otherwise aliphatic 4- to 6-membered ring), —S(O)₀₋₂—C₁₋₄alkyl,—SO₂N(R^(f))R^(g), —SCF₃, —C(O)C₁₋₄alkyl, —CN, —COOH, and —COOC₁₋₄alkyl;R^(c) and R^(d) are independently selected from the group consisting of—H, —C₁₋₇alkyl, —C₃₋₇alkenyl, —C₃₋₇alkynyl, —C₃₋₇cycloalkyl,—C₁₇alkylC₃₋₇cycloalkyl, and —C₃₋₇cycloalkylC₁₋₇alkyl, or R^(c) andR^(d) taken together with the nitrogen of attachment form piperidinyl,pyrrolidinyl, morpholinyl, thiomorpholinyl, or piperazinyl, where eachR^(c) and R^(d) is optionally and independently substituted with R^(e);R³ is —C₁₋₄alkyl, —C₁₋₄alkenyl, or benzyl, each optionally substitutedwith —C₁₋₃alkyl, —OH, or halo, or two R³ substituents taken togetherform C₂₋₅alkylene optionally substituted with —C₁₋₃alkyl, —OH, or halo;r is 0 or is an integer less than or equal to m+n+1; Ar is an aryl orheteroaryl ring selected from the group consisting of: a) phenyl,optionally mono-, di-, or tri-substituted with R^(i) or di-substitutedon adjacent carbons with —OC₁₋₄alkyleneO—, —(CH₂)₂₋₃NH—,—(CH₂)₁₋₂NH(CH₂)—, —(CH₂)₂₋₃N(C₁₋₄alkyl)-, or—(CH₂)₁₋₂N(C₁₋₄alkyl)(CH₂)—; R^(i) is selected from the group consistingof —C₁₋₇alkyl, —C₂₋₇alkenyl, —C₂₋₇alkynyl, —C₃₋₇cycloalkyl, halo, —CF₃,—OH, —OC₁₋₇alkyl, —OCF₃, —OC₃₋₇alkenyl, —OC₃₋₇alkynyl, —N(R^(j))R^(k)(wherein R^(j) and R^(k) are independently —H or —C₁₋₄alkyl),—C(O)N(R^(j))R^(k), —N(R^(j))C(O)R^(k), —N(R^(j))SO₂C₁₋₆alkyl,—S(O)₀₋₂—C₁₋₆alkyl, —SO₂N(R^(j))R^(k), —SCF₃, —C(O)C₁₋₆alkyl, —NO₂, —CN,—COOH, and —COOC₁₋₇alkyl; b) a monocyclic aromatic hydrocarbon grouphaving five ring atoms, having a carbon atom which is the point ofattachment, having one carbon atom replaced by >O, >S, >NH, or>N(C₁₋₄alkyl), having up to two additional carbon atoms optionallyreplaced by —N═, optionally mono- or di-substituted with R^(i); c) amonocyclic aromatic hydrocarbon group having six ring atoms, having acarbon atom which is the point of attachment, having one or two carbonatoms replaced by —N═, optionally mono- or di-substituted with R^(i);and d) phenyl or pyridyl, substituted with a substituent selected fromthe group consisting of phenyl, phenoxy, pyridyl, thiophenyl, oxazolyl,and tetrazolyl, where the resultant substituted moiety is optionallyfurther mono-, di-, or tri-substituted with R^(i); ALK is a branched orunbranched C₁₋₇alkylene, C₂₋₇alkenylene, C₂₋₇alkynylene,C₃₋₇cycloalkylene, or C₃₋₇cycloalkenylene, optionally mono-, di-, ortri-substituted with R^(m); R^(m) is selected from the group consistingof halo, —CF₃, —OH, —OC₁₋₇alkyl, —OC₃₋₇cycloalkyl, —OCF₃, —N(R^(p))R^(s)(wherein R^(p) and R^(s) are independently —H or —C₁₋₇alkyl),—C(O)N(R^(p))R^(s), —N(R^(t))C(O)R^(t), —N(R^(t))SO₂C₁₋₆alkyl (whereinR^(t) is —H or —C₁₋₇alkyl), —S(O)₀₋₂—C₁₋₆alkyl, —SO₂N(R^(p))R^(s),—SCF₃, —CN, —NO₂, —C(O)C₁₋₇alkyl, —COOH, and —COOC₁₋₇alkyl; CYC is —H oris a ring system selected from the group consisting of: i) phenyl,optionally mono-, di-, or tri-substituted with R^(u) or di-substitutedon adjacent carbons with —OC₁₋₄alkyleneO—, —(CH₂)₂₋₃NH—,—(CH₂)₁₋₂NH(CH₂)—, —(CH₂)₂₋₃N(C₁₋₄alkyl)-, or—(CH₂)₁₋₂N(C₁₋₄alkyl)(CH₂)—; R^(u) is selected from the group consistingof —C₁₋₇alkyl, —C₃₋₇cycloalkyl, phenyl, benzyl, halo, —CF₃, —OH,—OC₁₋₇alkyl, —OC₃₋₇cycloalkyl, —Ophenyl, —Obenzyl, —OCF₃, —N(R^(v))R^(w)(wherein R^(v) and R^(w) are independently —H or —C₁₋₇alkyl, or R^(v)and R^(w) taken together with the nitrogen of attachment formpiperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, or piperazinyl,where each R^(v) and R^(w) is optionally and independently substitutedwith —OH or —C₁₋₇alkyl), —C(O)N(R^(v))R^(w), —N(R^(x))C(O)R^(x),—N(R^(x))SO₂C₁₋₆alkyl (wherein R^(x) is —H or —C₁₋₇alkyl, or two R^(x)in the same substituent taken together with the amide of attachment forman otherwise aliphatic 4- to 6-membered ring), —N—(SO₂C₁₋₆alkyl)₂,—S(O)₀₋₂—C₁₋₆alkyl, —SO₂N(R^(v))R^(w), —SCF₃, —C(O)C₁₋₆alkyl, —NO₂, —CN,—COOH, and —COOC₁₋₇alkyl; ii) a monocyclic aromatic hydrocarbon grouphaving five ring atoms, having a carbon atom which is the point ofattachment, having one carbon atom replaced by >O, >S, >NH, or>N(C₁₋₄alkyl), having up to one additional carbon atoms optionallyreplaced by —N═, optionally mono- or di-substituted with R^(u); iii) amonocyclic aromatic hydrocarbon group having six ring atoms, having acarbon atom which is the point of attachment, having one or two carbonatoms replaced by —N═, optionally mono- or di-substituted with R^(u);and iv) a non-aromatic heterocyclic ring having 4 to 8 members, saidring having 0, 1, or 2 non-adjacent heteroatom members selected from thegroup consisting of O, S, —N═, >NH, and >N(C₁₋₄alkyl), having 0, 1, or 2double bonds, having 0, 1, or 2 carbon members which is a carbonyl,optionally having one carbon member which forms a bridge, having 0 to 5substituents R^(u), and where when q is 0, said ring has a carbon atomwhich is the point of attachment; and enantiomers, diastereomers,hydrates, solvates and pharmaceutically acceptable salts, esters andamides thereof; with the proviso that in Formula (I): (a) when ALK ismethylene, ethylene, propylene, or isopropylene, CYC is —H, Ar is phenylor mono-substituted phenyl, m is 2, n is 1, and A is >NR¹, then R¹ isnot —C₁₋₄alkyl or benzyl; (b) when q is 0, CYC is phenyl, Ar is phenylor 3-chlorophenyl, m is 2, and n is 1, then A is not unsubstituted—CH₂—; and (c) when q is 0, CYC is 2-pyridyl, Ar is 2-pyridyl, m is 2,and n is 1, then A is not unsubstituted —CH₂—.
 34. A method for thetreatment or prevention of a CNS disorder selected from the groupconsisting of: sleep disorders, depression/anxiety, generalized anxietydisorder, schizophrenia, bipolar disorders, psychotic disorders,obsessive-compulsive disorder, mood disorders, post-traumatic stress andother stress-related disorders, migraine, pain, eating disorders,obesity, sexual dysfunction, metabolic disturbances, hormonal imbalance,alcohol abuse, addictive disorders, nausea, inflammation, centrallymediated hypertension, sleep/wake disturbances, jetlag, and circadianrhythm abnormalities in mammals, comprising the step of administering toa mammal suffering there from an effective amount of at least onecompound of Formulae (I) or (II):

wherein m is 1, 2, or 3; n is 1, 2, or 3; where when m and n are bothpresent, m+n is greater than or equal to 2, and is less than or equal to4; R^(a) and R^(b) are independently —H, —C₁₋₇alkyl, or —C₃₋₇cycloalkyl,or R^(a) and R^(b) taken together with the nitrogen of attachment formpiperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, or piperazinyl,where each R^(a) and R^(b) is optionally and independently substitutedwith —C₁₋₄alkyl; q is 0 or 1; A is >NR¹, >CHNR^(c)R^(d), >CHOH, or—CH₂—, wherein R¹ is selected from the group consisting of —H,—C₁₋₇alkyl, —C₃₋₇cycloalkyl, and benzyl, where each alkyl, cycloalkyl,or benzyl is optionally mono-, di-, or tri-substituted with R^(e); R^(e)is selected from the group consisting of —C₁₋₄alkyl, —C₂₋₄alkenyl,—C₂₋₄alkynyl, —C₃₋₆cycloalkyl, halo, —CF₃, —OH, —OC₁₋₄alkyl, —OCF₃,—N(R^(f))R^(g) (wherein R^(f) and R^(g) are independently —H or—C₁₋₄alkyl, or R^(f) and R^(g) taken together with the nitrogen ofattachment form piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl,or piperazinyl), —C(O)N(R^(f))R^(g), —N(R^(h))C(O)R^(h),—N(R^(h))SO₂C₁₋₇alkyl (wherein R^(h) is —H or —C₁₋₄alkyl, or two R^(h)in the same substituent taken together with the amide of attachment forman otherwise aliphatic 4- to 6-membered ring), —S(O)₀₋₂—C₁₋₄alkyl,—SO₂N(R^(f))R^(g), —SCF₃, —C(O)C₁₋₄alkyl, —CN, —COOH, and —COOC₁₋₄alkyl;R^(c) and R^(d) are independently selected from the group consisting of—H, —C₁₋₇alkyl, —C₃₋₇alkenyl, —C₃₋₇alkynyl, —C₃₋₇cycloalkyl,—C₁₋₇alkylC₃₋₇cycloalkyl, and —C₃₋₇cycloalkylC₁₋₇alkyl, or R^(c) andR^(d) taken together with the nitrogen of attachment form piperidinyl,pyrrolidinyl, morpholinyl, thiomorpholinyl, or piperazinyl, where eachR^(c) and R^(d) is optionally and independently substituted with R^(e);R³ is —C₁₋₄alkyl, —C₁₋₄alkenyl, or benzyl, each optionally substitutedwith —C₁₋₃alkyl, —OH, or halo, or two R³ substituents taken togetherform C₂₋₅alkylene optionally substituted with —C₁₋₃alkyl, —OH, or halo;r is 0 or is an integer less than or equal to m+n+1; Ar is an aryl orheteroaryl ring selected from the group consisting of: a) phenyl,optionally mono-, di-, or tri-substituted with R^(i) or di-substitutedon adjacent carbons with —OC₁₋₄alkyleneO—, —(CH₂)₂₋₃NH—,—(CH₂)₁₋₂NH(CH₂)—, —(CH₂)₂₋₃N(C₁₋₄alkyl)-, or—(CH₂)₁₋₂N(C₁₋₄alkyl)(CH₂)—; R^(i) is selected from the group consistingof —C₁₋₇alkyl, —C₂₋₇alkenyl, —C₂₋₇alkynyl, —C₃₋₇cycloalkyl, halo, —CF₃,—OH, —OC₁₋₇alkyl, —OCF₃, —OC₃₋₇alkenyl, —OC₃₋₇alkynyl, —N(R^(j))R^(k)(wherein R^(j) and R^(k) are independently —H or —C₁₋₄alkyl),—C(O)N(R^(j))R^(k), —N(R^(j))C(O)R^(k), —N(R^(j))SO₂C₁₋₆alkyl—S(O)₀₋₂—C₁₋₆alkyl, —SO₂N(R^(j))R^(k), —SCF₃, —C(O)C₁₋₆alkyl, —NO₂, —CN,—COOH, and —COOC₁₋₇alkyl; b) a monocyclic aromatic hydrocarbon grouphaving five ring atoms, having a carbon atom which is the point ofattachment, having one carbon atom replaced by >O, >S, >NH, or>N(C₁₋₄alkyl), having up to two additional carbon atoms optionallyreplaced by —N═, optionally mono- or di-substituted with R^(i); c) amonocyclic aromatic hydrocarbon group having six ring atoms, having acarbon atom which is the point of attachment, having one or two carbonatoms replaced by —N═, optionally mono- or di-substituted with R^(i);and d) phenyl or pyridyl, substituted with a substituent selected fromthe group consisting of phenyl, phenoxy, pyridyl, thiophenyl, oxazolyl,and tetrazolyl, where the resultant substituted moiety is optionallyfurther mono-, di-, or tri-substituted with R^(i); ALK is a branched orunbranched C₁₋₇alkylene, C₂₋₇alkenylene, C₂₋₇alkynylene,C₃₋₇cycloalkylene, or C₃₋₇cycloalkenylene, optionally mono-, di-, ortri-substituted with R^(m); R^(m) is selected from the group consistingof halo, —CF₃, —OH, —OC₁₋₇alkyl, —OC₃₋₇cycloalkyl, —OCF₃, —N(R^(p))R^(s)(wherein R^(p) and R^(s) are independently —H or —C₁₋₇alkyl),—C(O)N(R^(p))R^(s), —N(R^(t))C(O)R^(t), —N(R^(t))SO₂C₁₋₆alkyl (whereinR^(t) is —H or —C₁₋₇alkyl), —S(O)₀₋₂—C₁₋₆alkyl, —SO₂N(R^(p))R^(s),—SCF₃, —CN, —NO₂, —C(O)C₁₋₇alkyl, —COOH, and —COOC₁₋₇alkyl; CYC is —H oris a ring system selected from the group consisting of: i) phenyl,optionally mono-, di-, or tri-substituted with R^(u) or di-substitutedon adjacent carbons with —OC₁₋₄alkyleneO—, —(CH₂)₂₋₃NH—,—(CH₂)₁₋₂NH(CH₂)—, —(CH₂)₂₋₃N(C₁₋₄alkyl)-, or—(CH₂)₁₋₂N(C₁₋₄alkyl)(CH₂)—; R^(u) is selected from the group consistingof —C₁₋₇alkyl, —C₃₋₇cycloalkyl, phenyl, benzyl, halo, —CF₃, —OH,—OC₁₋₇alkyl, —OC₃₋₇cycloalkyl, —Ophenyl, —Obenzyl, —OCF₃, —N(R^(v))R^(w)(wherein R^(v) and R^(w) are independently —H or —C₁₋₇alkyl, or R^(v)and R^(w) taken together with the nitrogen of attachment formpiperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, or piperazinyl,where each R^(v) and R^(w) is optionally and independently substitutedwith —OH or —C₁₋₇alkyl), —C(O)N(R^(v))R^(w), —N(R^(x))C(O)R^(x),—N(R^(x))SO₂C₁₋₆alkyl (wherein R^(x) is —H or —C₁₋₇alkyl, or two R^(x)in the same substituent taken together with the amide of attachment forman otherwise aliphatic 4- to 6-membered ring), —N—(SO₂C₁₋₆alkyl)₂,—S(O)₀₋₂—C₁₋₆alkyl, —SO₂N(R^(v))R^(w), —SCF₃, —C(O)C₁₋₆alkyl), —NO₂,—CN, —COOH, and —COOC₁₋₇alkyl; ii) a monocyclic aromatic hydrocarbongroup having five ring atoms, having a carbon atom which is the point ofattachment, having one carbon atom replaced by >O, >S, >NH, or>N(C₁₋₄alkyl), having up to one additional carbon atoms optionallyreplaced by —N═, optionally mono- or di-substituted with R^(u); iii) amonocyclic aromatic hydrocarbon group having six ring atoms, having acarbon atom which is the point of attachment, having one or two carbonatoms replaced by —N═, optionally mono- or di-substituted with R^(u);and iv) a non-aromatic heterocyclic ring having 4 to 8 members, saidring having 0, 1, or 2 non-adjacent heteroatom members selected from thegroup consisting of O, S, —N═, >NH, and >N(C₁₋₄alkyl), having 0, 1, or 2double bonds, having 0, 1, or 2 carbon members which is a carbonyl,optionally having one carbon member which forms a bridge, having 0 to 5substituents R^(u), and where when q is 0, said ring has a carbon atomwhich is the point of attachment; and enantiomers, diastereomers,hydrates, solvates and pharmaceutically acceptable salts, esters andamides thereof.
 35. The method of claim 34 wherein said CNS disorder isselected from the group consisting of: depression/anxiety, sleepdisorders, and circadian rhythm abnormalities.
 36. A method for thetreatment or prevention of a disease or condition selected from thegroup consisting of: hypotension, peripheral vascular disorders,cardiovascular shock, renal disorders, gastric motility, diarrhea,spastic colon, irritable bowel disorders, ischemias, septic shock,urinary incontinence, and other disorders related to thegastrointestinal and vascular systems in mammals, comprising the step ofadministering to a mammal suffering there from an effective amount of atleast one compound of Formulae (I) or (II):

wherein m is 1, 2, or 3; n is 1, 2, or 3; where when m and n are bothpresent, m+n is greater than or equal to 2, and is less than or equal to4; R^(a) and R^(b) are independently —H, —C₁₋₇alkyl, or —C₃₋₇cycloalkyl,or R^(a) and R^(b) taken together with the nitrogen of attachment formpiperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, or piperazinyl,where each R^(a) and R^(b) is optionally and independently substitutedwith —C₁₋₄alkyl; q is 0 or 1; A is >NR¹, >CHNR^(c)R^(d), >CHOH, or—CH₂—, wherein R¹ is selected from the group consisting of —H,—C₁₋₇alkyl, —C₃₋₇cycloalkyl, and benzyl, where each alkyl, cycloalkyl,or benzyl is optionally mono-, di-, or tri-substituted with R^(e); R^(e)is selected from the group consisting of —C₁₋₄alkyl, —C₂₋₄alkenyl,—C₂₋₄alkynyl, —C₃₋₆cycloalkyl, halo, —CF₃, —OH, —OC₁₋₄alkyl, —OCF₃,—N(R^(f))R^(g) (wherein R^(f) and R^(g) are independently —H or—C₁₋₄alkyl, or R^(f) and R^(g) taken together with the nitrogen ofattachment form piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl,or piperazinyl), —C(O)N(R^(f))R^(g), —N(R^(h))C(O)R^(h),—N(R^(h))SO₂C₁₋₇alkyl (wherein R^(h) is —H or —C₁₋₄alkyl, or two R^(h)in the same substituent taken together with the amide of attachment forman otherwise aliphatic 4- to 6-membered ring), —S(O)₀₋₂—C₁₋₄alkyl,—SO₂N(R^(f))R^(g), —SCF₃, —C(O)C₁₋₄alkyl, —CN, —COOH, and —COOC₁₋₄alkyl;R^(c) and R^(d) are independently selected from the group consisting of—H, —C₁₋₇alkyl, —C₃₋₇alkenyl, —C₃₋₇alkynyl, —C₃₋₇cycloalkyl,—C₁₋₇alkylC₃₋₇cycloalkyl, and —C₃₋₇cycloalkylC₁₋₇alkyl, or R^(c) andR^(d) taken together with the nitrogen of attachment form piperidinyl,pyrrolidinyl, morpholinyl, thiomorpholinyl, or piperazinyl, where eachR^(c) and R^(d) is optionally and independently substituted with R^(e);R³ is —C₁₋₄alkyl, —C₁₋₄alkenyl, or benzyl, each optionally substitutedwith —C₁₋₃alkyl, —OH, or halo, or two R³ substituents taken togetherform C₂₋₅alkylene optionally substituted with —C₁₋₃alkyl, —OH, or halo;r is 0 or is an integer less than or equal to m+n+1; Ar is an aryl orheteroaryl ring selected from the group consisting of: a) phenyl,optionally mono-, di-, or tri-substituted with R^(i) or di-substitutedon adjacent carbons with —OC₁₋₄alkyleneO—, —(CH₂)₂₋₃NH—,—(CH₂)₁₋₂NH(CH₂)—, —(CH₂)₂₋₃N(C₁₋₄alkyl)-, or—(CH₂)₁₋₂N(C₁₋₄alkyl)(CH₂)—; R^(i) is selected from the group consistingof —C₁₋₇alkyl, —C₂₋₇alkenyl, —C₂₋₇alkynyl, —C₃₋₇cycloalkyl, halo, —CF₃,—OH, —OC₁₋₇alkyl, —OCF₃, —OC₃₋₇alkenyl, —OC₃₋₇alkynyl, —N(R^(j))R^(k)(wherein R^(j) and R^(k) are independently —H or —C₁₋₄alkyl),—C(O)N(R^(j))R^(k), —N(R^(j))C(O)R^(k), —N(R^(j))SO₂C₁₋₆alkyl,—S(O)₀₋₂—C₁₋₆alkyl, —SO₂N(R^(j))R^(k), —SCF₃, —C(O)C₁₋₆alkyl, —NO₂, —CN,—COOH, and —COOC₁₋₇alkyl; b) a monocyclic aromatic hydrocarbon grouphaving five ring atoms, having a carbon atom which is the point ofattachment, having one carbon atom replaced by >O, >S, >NH, or>N(C₁₋₄alkyl), having up to two additional carbon atoms optionallyreplaced by —N═, optionally mono- or di-substituted with R^(i); c) amonocyclic aromatic hydrocarbon group having six ring atoms, having acarbon atom which is the point of attachment, having one or two carbonatoms replaced by —N═, optionally mono- or di-substituted with R^(i);and d) phenyl or pyridyl, substituted with a substituent selected fromthe group consisting of phenyl, phenoxy, pyridyl, thiophenyl, oxazolyl,and tetrazolyl, where the resultant substituted moiety is optionallyfurther mono-, di-, or tri-substituted with R^(i); ALK is a branched orunbranched C₁₋₇alkylene, C₂₋₇alkenylene, C₂₋₇alkynylene,C₃₋₇cycloalkylene, or C₃₋₇cycloalkenylene, optionally mono-, di-, ortri-substituted with R^(m); R^(m) is selected from the group consistingof halo, —CF₃, —OH, —OC₁₋₇alkyl, —OC₃₋₇cycloalkyl, —OCF₃, —N(R^(p))R^(s)(wherein R^(p) and R^(s) are independently —H or —C₁₋₇alkyl),—C(O)N(R^(p))R^(s), —N(R^(t))C(O)R^(t), —N(R^(t))SO₂C₁₋₆alkyl (whereinR^(t) is —H or —C₁₋₇alkyl), —S(O)₀₋₂—C₁₋₆alkyl, —SO₂N(R^(p))R^(s),—SCF₃, —CN, —NO₂, —C(O)C₁₋₇alkyl, —COOH, and —COOC₁₋₇alkyl; CYC is —H oris a ring system selected from the group consisting of: i) phenyl,optionally mono-, di-, or tri-substituted with R^(u) or di-substitutedon adjacent carbons with —OC₁₋₄alkyleneO—, —(CH₂)₂₋₃NH—,—(CH₂)₁₋₂NH(CH₂)—, —(CH₂)₂₋₃N(C₁₋₄alkyl)-, or—(CH₂)₁₋₂N(C₁₋₄alkyl)(CH₂)—; R^(u) is selected from the group consistingof —C₁₋₇alkyl, —C₃₋₇cycloalkyl, phenyl, benzyl, halo, —CF₃, —OH,—OC₁₋₇alkyl, —OC₃₋₇cycloalkyl, —Ophenyl, —Obenzyl, —OCF₃, —N(R^(v))R^(w)(wherein R^(v) and R^(w) are independently —H or —C₁₋₇alkyl, or R^(v)and R^(w) taken together with the nitrogen of attachment formpiperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, or piperazinyl,where each R^(v) and R^(w) is optionally and independently substitutedwith —OH or —C₁₋₇alkyl), —C(O)N(R^(v))R^(w), —N(R^(x))C(O)R^(x),—N(R^(x))SO₂C₁₋₆alkyl (wherein R^(x) is —H or —C₁₋₇alkyl, or two R^(x)in the same substituent taken together with the amide of attachment forman otherwise aliphatic 4- to 6-membered ring), —N—(SO₂C₁₋₆alkyl)₂,—S(O)₀₋₂—C₁₋₆alkyl, —SO₂N(R^(v))R^(w), —SCF₃, —C(O)C_(—NO) ₂, —CN,—COOH, and —COOC₁₋₇alkyl; ii) a monocyclic aromatic hydrocarbon grouphaving five ring atoms, having a carbon atom which is the point ofattachment, having one carbon atom replaced by >O, >S, >NH, or>N(C₁₋₄alkyl), having up to one additional carbon atoms optionallyreplaced by —N═, optionally mono- or di-substituted with R^(u); iii) amonocyclic aromatic hydrocarbon group having six ring atoms, having acarbon atom which is the point of attachment, having one or two carbonatoms replaced by —N═, optionally mono- or di-substituted with R^(u);and iv) a non-aromatic heterocyclic ring having 4 to 8 members, saidring having 0, 1, or 2 non-adjacent heteroatom members selected from thegroup consisting of O, S, —N═, >NH, and >N(C₁₋₄alkyl), having 0, 1, or 2double bonds, having 0, 1, or 2 carbon members which is a carbonyl,optionally having one carbon member which forms a bridge, having 0 to 5substituents R^(u), and where when q is 0, said ring has a carbon atomwhich is the point of attachment; and enantiomers, diastereomers,hydrates, solvates and pharmaceutically acceptable salts, esters andamides thereof.
 37. A method for the treatment or prevention of anocular disorder selected from the group consisting of: glaucoma, opticneuritis, diabetic retinopathy, retinal edema, and age-related maculardegeneration in mammals, comprising the step of administering to amammal suffering there from an effective amount of at least one compoundof Formulae (I) or (II):

wherein m is 1, 2, or 3; n is 1, 2, or 3; where when m and n are bothpresent, m+n is greater than or equal to 2, and is less than or equal to4; R^(a) and R^(b) are independently —H, —C₁₋₇alkyl, or —C₃₋₇cycloalkyl,or R^(a) and R^(b) taken together with the nitrogen of attachment formpiperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, or piperazinyl,where each R^(a) and R^(b) is optionally and independently substitutedwith —C₁₋₄alkyl; q is 0 or 1; A is >NR¹, >CHNR^(c)R^(d), >CHOH, or—CH₂—, wherein R¹ is selected from the group consisting of —H,—C₁₋₇alkyl, —C₃₋₇cycloalkyl, and benzyl, where each alkyl, cycloalkyl,or benzyl is optionally mono-, di-, or tri-substituted with R^(e); R^(e)is selected from the group consisting of —C₁₋₄alkyl, —C₂₋₄alkenyl,—C₂₋₄alkynyl, —C₃₋₆cycloalkyl, halo, —CF₃, —OH, —OC₁₋₄alkyl, —OCF₃,—N(R^(f))R^(g) (wherein R^(f) and R^(g) are independently —H or—C₁₋₄alkyl, or R^(f) and R^(g) taken together with the nitrogen ofattachment form piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl,or piperazinyl), —C(O)N(R^(f))R^(g), —N(R^(h))C(O)R^(h),—N(R^(h))SO₂C₁₋₇alkyl (wherein R^(h) is —H or —C₁₋₄alkyl, or two R^(h)in the same substituent taken together with the amide of attachment forman otherwise aliphatic 4- to 6-membered ring), —S(O)₀₋₂—C₁₋₄alkyl,—SO₂N(R^(f))R^(g), —SCF₃, —C(O)C₁₋₄alkyl, —CN, —COOH, and —COOC₁₋₄alkyl;R^(c) and R^(d) are independently selected from the group consisting of—H, —C₁₋₇alkyl, —C₃₋₇alkenyl, —C₃₋₇alkynyl, —C₃₋₇cycloalkyl,—C₁₋₇alkylC₃₋₇cycloalkyl, and —C₃₋₇cycloalkylC₁₋₇alkyl, or R^(c) andR^(d) taken together with the nitrogen of attachment form piperidinyl,pyrrolidinyl, morpholinyl, thiomorpholinyl, or piperazinyl, where eachR^(c) and R^(d) is optionally and independently substituted with R^(e);R³ is —C₁₋₄alkyl, —C₁₋₄alkenyl, or benzyl, each optionally substitutedwith —C₁₋₃alkyl, —OH, or halo, or two R³ substituents taken togetherform C₂₋₅alkylene optionally substituted with —C₁₋₃alkyl, —OH, or halo;r is 0 or is an integer less than or equal to m+n+1; Ar is an aryl orheteroaryl ring selected from the group consisting of: a) phenyl,optionally mono-, di-, or tri-substituted with R^(i) or di-substitutedon adjacent carbons with —OC₁₋₄alkyleneO—, —(CH₂)₂₋₃NH—,—(CH₂)₁₋₂NH(CH₂)—, —(CH₂)₂₋₃N(C₁₋₄alkyl)-, or—(CH₂)₁₋₂N(C₁₋₄alkyl)(CH₂)—; R^(i) is selected from the group consistingof —C₁₋₇alkyl, —C₂₋₇alkenyl, —C₂₋₇alkynyl, —C₃₋₇cycloalkyl, halo, —CF₃,—OH, —OC₁₋₇alkyl, —OCF₃, —OC₃₋₇alkenyl, —OC₃₋₇alkynyl, —N(R^(j))R^(k)(wherein R^(j) and R^(k) are independently —H or —C₁₋₄alkyl),—C(O)N(R^(j))R^(k), —N(R^(j))C(O)R^(k), —N(R^(j))SO₂C₁₋₆alkyl,—S(O)₀₋₂—C₁₋₆alkyl, —SO₂N(R^(j))R^(k), —SCF₃, —C(O)C₁₋₆alkyl, —NO₂, —CN,—COOH, and —COOC₁₋₇alkyl; b) a monocyclic aromatic hydrocarbon grouphaving five ring atoms, having a carbon atom which is the point ofattachment, having one carbon atom replaced by >O, >S, >NH, or>N(C₁₋₄alkyl), having up to two additional carbon atoms optionallyreplaced by —N═, optionally mono- or di-substituted with R^(i); c) amonocyclic aromatic hydrocarbon group having six ring atoms, having acarbon atom which is the point of attachment, having one or two carbonatoms replaced by —N═, optionally mono- or di-substituted with R^(i);and d) phenyl or pyridyl, substituted with a substituent selected fromthe group consisting of phenyl, phenoxy, pyridyl, thiophenyl, oxazolyl,and tetrazolyl, where the resultant substituted moiety is optionallyfurther mono-, di-, or tri-substituted with R^(i); ALK is a branched orunbranched C₁₋₇alkylene, C₂₋₇alkenylene, C₂₋₇alkynylene,C₃₋₇cycloalkylene, or C₃₋₇cycloalkenylene, optionally mono-, di-, ortri-substituted with R^(m); R^(m) is selected from the group consistingof halo, —CF₃, —OH, —OC₁₋₇alkyl, —OC₃₋₇cycloalkyl, —OCF₃, —N(R^(p))R^(s)(wherein R^(p) and R^(s) are independently —H or —C₁₋₇alkyl),—C(O)N(R^(p))R^(s), —N(R^(t))C(O)R^(t), —N(R^(t))SO₂C₁₋₆alkyl (whereinR^(t) is —H or —C₁₋₇alkyl), —S(O)₀₋₂—C₁₋₆alkyl, —SO₂N(R^(p))R^(s),—SCF₃, —CN, —NO₂, —C(O)C₁₋₇alkyl, —COOH, and —COOC₁₋₇alkyl; CYC is —H oris a ring system selected from the group consisting of: i) phenyl,optionally mono-, di-, or tri-substituted with R^(u) or di-substitutedon adjacent carbons with —OC₁₋₄alkyleneO—, —(CH₂)₂₋₃NH—,—(CH₂)₁₋₂NH(CH₂)—, —(CH₂)₂₋₃N(C₁₋₄alkyl)-, or—(CH₂)₁₋₂N(C₁₋₄alkyl)(CH₂)—; R^(u) is selected from the group consistingof —C₁₋₇alkyl, —C₃₋₇cycloalkyl, phenyl, benzyl, halo, —CF₃, —OH,—OC₁₋₇alkyl, —OC₃₋₇cycloalkyl, —Ophenyl, —Obenzyl, —OCF₃, —N(R^(v))R^(w)(wherein R^(v) and R^(w) are independently —H or —C₁₋₇alkyl, or R^(v)and R^(w) taken together with the nitrogen of attachment formpiperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, or piperazinyl,where each R^(v) and R^(w) is optionally and independently substitutedwith —OH or —C₁₋₇alkyl), —C(O)N(R^(v))R^(w), —N(R^(x))C(O)R^(x),—N(R^(x))SO₂C₁₋₆alkyl (wherein R^(x) is —H or —C₁₋₇alkyl, or two R^(x)in the same substituent taken together with the amide of attachment forman otherwise aliphatic 4- to 6-membered ring), —N—(SO₂C₁₋₆alkyl)₂,—S(O)₀₋₂—C₁₋₆alkyl, —SO₂N(R^(v))R^(w), —SCF₃, —C(O)C₁₋₆alkyl, —NO₂, —CN,—COOH, and —COOC₁₋₇alkyl; ii) a monocyclic aromatic hydrocarbon grouphaving five ring atoms, having a carbon atom which is the point ofattachment, having one carbon atom replaced by >O, >S, >NH, or>N(C₁₋₄alkyl), having up to one additional carbon atoms optionallyreplaced by —N═, optionally mono- or di-substituted with R^(u); iii) amonocyclic aromatic hydrocarbon group having six ring atoms, having acarbon atom which is the point of attachment, having one or two carbonatoms replaced by —N═, optionally mono- or di-substituted with R^(u);and iv) a non-aromatic heterocyclic ring having 4 to 8 members, saidring having 0, 1, or 2 non-adjacent heteroatom members selected from thegroup consisting of O, S, —N═, >NH, and >N(C₁₋₄alkyl), having 0, 1, or 2double bonds, having 0, 1, or 2 carbon members which is a carbonyl,optionally having one carbon member which forms a bridge, having 0 to 5substituents R^(u), and where when q is 0, said ring has a carbon atomwhich is the point of attachment; and enantiomers, diastereomers,hydrates, solvates and pharmaceutically acceptable salts, esters andamides thereof.
 38. A method for the treatment or prevention of adisease or condition selected from the group consisting of:depression/anxiety, sleep/wake disturbances, jetlag, migraine, urinaryincontinence, gastric motility, and irritable bowel disorders inmammals, comprising the step of administering to a mammal sufferingthere from an effective amount of at least one compound of Formulae (I)or (II):

wherein m is 1, 2, or 3; n is 1, 2, or 3; where when m and n are bothpresent, m+n is greater than or equal to 2, and is less than or equal to4; R^(a) and R^(b) are independently —H, —C₁₋₇alkyl, or —C₃₋₇cycloalkyl,or R^(a) and R^(b) taken together with the nitrogen of attachment formpiperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, or piperazinyl,where each R^(a) and R^(b) is optionally and independently substitutedwith —C₁₋₄alkyl; q is 0 or 1; A is >NR¹, >CHNR^(c)R^(d), >CHOH, or—CH₂—, wherein R¹ is selected from the group consisting of —H,—C₁₋₇alkyl, —C₃₋₇cycloalkyl, and benzyl, where each alkyl, cycloalkyl,or benzyl is optionally mono-, di-, or tri-substituted with R^(e); R^(e)is selected from the group consisting of —C₁₋₄alkyl, —C₂₋₄alkenyl,—C₂₋₄alkynyl, —C₃₋₆cycloalkyl, halo, —CF₃, —OH, —OC₁₋₄alkyl, —OCF₃,—N(R^(f))R^(g) (wherein R^(f) and R^(g) are independently —H or—C₁₋₄alkyl, or R^(f) and R^(g) taken together with the nitrogen ofattachment form piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl,or piperazinyl), —C(O)N(R^(f))R^(g), —N(R^(h))C(O)R^(h), —N(R^(h))SO₂C₁₋₇alkyl (wherein R^(h) is —H or —C₁₋₄alkyl, or two R^(h) in thesame substituent taken together with the amide of attachment form anotherwise aliphatic 4- to 6-membered ring), —S(O)₀₋₂—C₁₋₄alkyl,—SO₂N(R^(f))R^(g), —SCF₃, —C(O)C₁₋₄alkyl, —CN, —COOH, and —COOC₁₋₄alkyl;R^(c) and R^(d) are independently selected from the group consisting of—H, —C₁₋₇alkyl, —C₃₋₇alkenyl, —C₃₋₇alkynyl, —C₃₋₇cycloalkyl,—C₁₋₇alkylC₃₋₇cycloalkyl, and —C₃₋₇cycloalkylC₁₋₇alkyl, or R^(c) andR^(d) taken together with the nitrogen of attachment form piperidinyl,pyrrolidinyl, morpholinyl, thiomorpholinyl, or piperazinyl, where eachR^(c) and R^(d) is optionally and independently substituted with R^(e);R³ is —C₁₋₄alkyl, —C₁₋₄alkenyl, or benzyl, each optionally substitutedwith —C₁₋₃alkyl, —OH, or halo, or two R³ substituents taken togetherform C₂₋₅alkylene optionally substituted with —C₁₋₃alkyl, —OH, or halo;r is 0 or is an integer less than or equal to m+n+1; Ar is an aryl orheteroaryl ring selected from the group consisting of: a) phenyl,optionally mono-, di-, or tri-substituted with R^(i) or di-substitutedon adjacent carbons with —OC₁₋₄alkyleneO—, —(CH₂)₂₋₃NH—,—(CH₂)₁₋₂NH(CH₂)—, —(CH₂)₂₋₃N(C₁₋₄alkyl)-, or—(CH₂)₁₋₂N(C₁₋₄alkyl)(CH₂)—; R^(i) is selected from the group consistingof —C₁₋₇alkyl, —C₂₋₇alkenyl, —C₂₋₇alkynyl, —C₃₋₇cycloalkyl, halo, —CF₃,—OH, —OC₁₋₇alkyl, —OCF₃, —OC₃₋₇alkenyl, —OC₃₋₇alkynyl, —N(R^(j))R^(k)(wherein R^(j) and R^(k) are independently —H or —C₁₋₄alkyl),—C(O)N(R^(j))R^(k), —N(R^(j))C(O)R^(k), —N(R^(j))SO₂C₁₋₆alkyl,—S(O)₀₋₂—C₁₋₆alkyl, —SO₂N(R^(j))R^(k), —SCF₃, —C(O)C₁₋₆alkyl, —NO₂, —CN,—COOH, and —COOC₁₋₇alkyl; b) a monocyclic aromatic hydrocarbon grouphaving five ring atoms, having a carbon atom which is the point ofattachment, having one carbon atom replaced by >O, >S, >NH, or>N(C₁₋₄alkyl), having up to two additional carbon atoms optionallyreplaced by —N═, optionally mono- or di-substituted with R^(i); c) amonocyclic aromatic hydrocarbon group having six ring atoms, having acarbon atom which is the point of attachment, having one or two carbonatoms replaced by —N═, optionally mono- or di-substituted with R^(i);and d) phenyl or pyridyl, substituted with a substituent selected fromthe group consisting of phenyl, phenoxy, pyridyl, thiophenyl, oxazolyl,and tetrazolyl, where the resultant substituted moiety is optionallyfurther mono-, di-, or tri-substituted with R^(i); ALK is a branched orunbranched C₁₋₇alkylene, C₂₋₇alkenylene, C₂₋₇alkynylene,C₃₋₇cycloalkylene, or C₃₋₇cycloalkenylene, optionally mono-, di-, ortri-substituted with R^(m); R^(m) is selected from the group consistingof halo, —CF₃, —OH, —OC₁₋₇alkyl, —OC₃₋₇cycloalkyl, —OCF₃, —N(R^(p))R^(s)(wherein R^(p) and R^(s) are independently —H or —C₁₋₇alkyl),—C(O)N(R^(p))R^(s), —N(R^(t))C(O)R^(t), —N(R^(t))SO₂C₁₋₆alkyl (whereinR^(t) is —H or —C₁₋₇alkyl), —S(O)₀₋₂—C₁₋₆alkyl, —SO₂N(R^(p))R^(s),—SCF₃, —CN, —NO₂, —C(O)C₁₋₇alkyl, —COOH, and —COOC₁₋₇alkyl; CYC is —H oris a ring system selected from the group consisting of: i) phenyl,optionally mono-, di-, or tri-substituted with R^(u) or di-substitutedon adjacent carbons with —OC₁₋₄alkyleneO—, —(CH₂)₂₋₃NH—,—(CH₂)₁₋₂NH(CH₂)—, —(CH₂)₂₋₃N(C₁₋₄alkyl)-, or—(CH₂)₁₋₂N(C₁₋₄alkyl)(CH₂)—; R^(u) is selected from the group consistingof —C₁₋₇alkyl, —C₃₋₇cycloalkyl, phenyl, benzyl, halo, —CF₃, —OH,—OC₁₋₇alkyl, —OC₃₋₇cycloalkyl, —Ophenyl, —Obenzyl, —OCF₃, —N(R^(v))R^(w)(wherein R^(v) and R^(w) are independently —H or —C₁₋₇alkyl, or R^(v)and R^(w) taken together with the nitrogen of attachment formpiperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, or piperazinyl,where each R^(v) and R^(w) is optionally and independently substitutedwith —OH or —C₁₋₇alkyl), —C(O)N(R^(v))R^(w), —N(R^(x))C(O)R^(x),—N(R^(x))SO₂C₁₋₆alkyl (wherein R^(x) is —H or —C₁₋₇alkyl, or two R^(x)in the same substituent taken together with the amide of attachment forman otherwise aliphatic 4- to 6-membered ring), —N—(SO₂C₁₋₆alkyl)₂,—S(O)₀₋₂—C₁₋₆alkyl, —SO₂N(R^(v))R^(w), —SCF₃, —C(O)C₁₋₆alkyl, —NO₂, —CN,—COOH, and —COOC₁₋₇alkyl; ii) a monocyclic aromatic hydrocarbon grouphaving five ring atoms, having a carbon atom which is the point ofattachment, having one carbon atom replaced by >O, >S, >NH, or>N(C₁₋₄alkyl), having up to one additional carbon atoms optionallyreplaced by —N═, optionally mono- or di-substituted with R^(u); iii) amonocyclic aromatic hydrocarbon group having six ring atoms, having acarbon atom which is the point of attachment, having one or two carbonatoms replaced by —N═, optionally mono- or di-substituted with R^(u);and iv) a non-aromatic heterocyclic ring having 4 to 8 members, saidring having 0, 1, or 2 non-adjacent heteroatom members selected from thegroup consisting of O, S, —N═, >NH, and >N(C₁₋₄alkyl), having 0, 1, or 2double bonds, having 0, 1, or 2 carbon members which is a carbonyl,optionally having one carbon member which forms a bridge, having 0 to 5substituents R^(u), and where when q is 0, said ring has a carbon atomwhich is the point of attachment; and enantiomers, diastereomers,hydrates, solvates and pharmaceutically acceptable salts, esters andamides thereof.
 39. A method for the treatment or prevention of adisease or condition selected from the group consisting of:depression/anxiety, generalized anxiety disorder, schizophrenia, bipolardisorders, psychotic disorders, obsessive-compulsive disorder, mooddisorders, post-traumatic stress disorders, sleep disturbances, sexualdysfunction, eating disorders, migraine, addictive disorders, andperipheral vascular disorders in mammals, comprising the step ofadministering to a mammal suffering there from an effective amount of atleast one compound of Formulae (I) or (II):

wherein m is 1, 2, or 3; n is 1, 2, or 3; where when m and n are bothpresent, m+n is greater than or equal to 2, and is less than or equal to4; R^(a) and R^(b) are independently —H, —C₁₋₇alkyl, or —C₃₋₇cycloalkyl,or R^(a) and R^(b) taken together with the nitrogen of attachment formpiperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, or piperazinyl,where each R^(a) and R^(b) is optionally and independently substitutedwith —C₁₋₄alkyl; q is 0 or 1; A is >NR¹, >CHNR^(c)R^(d), >CHOH, or—CH₂—, wherein R¹ is selected from the group consisting of —H,—C₁₋₇alkyl, —C₃₋₇cycloalkyl, and benzyl, where each alkyl, cycloalkyl,or benzyl is optionally mono-, di-, or tri-substituted with R^(e); R^(e)is selected from the group consisting of —C₁₋₄alkyl, —C₂₋₄alkenyl,—C₂₋₄alkynyl, —C₃₋₆cycloalkyl, halo, —CF₃, —OH, —OC₁₋₄alkyl, —OCF₃,—N(R^(f))R^(g) (wherein R^(f) and R^(g) are independently —H or—C₁₋₄alkyl, or R^(f) and R^(g) taken together with the nitrogen ofattachment form piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl,or piperazinyl), —C(O)N(R^(f))R^(g), —N(R^(h))C(O)R^(h), —N(R^(h))SO₂C₁₋₇alkyl (wherein R^(h) is —H or —C₁₋₄alkyl, or two R^(h) in thesame substituent taken together with the amide of attachment form anotherwise aliphatic 4- to 6-membered ring), —S(O)₀₋₂—C₁₋₄alkyl,—SO₂N(R^(f))R^(g), —SCF₃, —C(O)C₁₋₄alkyl, —CN, —COOH, and —COOC₁₋₄alkyl;R^(c) and R^(d) are independently selected from the group consisting of—H, —C₁₋₇alkyl, —C₃₋₇alkenyl, —C₃₋₇alkynyl, —C₃₋₇cycloalkyl,—C₁₋₇alkylC₃₋₇cycloalkyl, and —C₃₋₇cycloalkylC₁₋₇alkyl, or R^(c) andR^(d) taken together with the nitrogen of attachment form piperidinyl,pyrrolidinyl, morpholinyl, thiomorpholinyl, or piperazinyl, where eachR^(c) and R^(d) is optionally and independently substituted with R^(e);R³ is —C₁₋₄alkyl, —C₁₋₄alkenyl, or benzyl, each optionally substitutedwith —C₁₋₃alkyl, —OH, or halo, or two R³ substituents taken togetherform C₂₋₅alkylene optionally substituted with —C₁₋₃alkyl, —OH, or halo;r is 0 or is an integer less than or equal to m+n+1; Ar is an aryl orheteroaryl ring selected from the group consisting of: a) phenyl,optionally mono-, di-, or tri-substituted with R^(i) or di-substitutedon adjacent carbons with —OC₁₋₄alkyleneO—, —(CH₂)₂₋₃NH—,—(CH₂)₁₋₂NH(CH₂)—, —(CH₂)₂₋₃N(C₁₋₄alkyl)-, or—(CH₂)₁₋₂N(C₁₋₄alkyl)(CH₂)—; R^(i) is selected from the group consistingof —C₁₋₇alkyl, —C₂₋₇alkenyl, —C₂₋₇alkynyl, —C₃₋₇cycloalkyl, halo, —CF₃,—OH, —OC₁₋₇alkyl, —OCF₃, —OC₃₋₇alkenyl, —OC₃₋₇alkynyl, —N(R^(j))R^(k)(wherein R^(j) and R^(k) are independently —H or —C₁₋₄alkyl),—C(O)N(R^(j))R^(k), —N(R^(j))C(O)R^(k), —N(R^(j))SO₂C₁₋₆alkyl,—S(O)₀₋₂—C₁₋₆alkyl, —SO₂N(R^(j))R^(k), —SCF₃, —C(O)C₁₋₆alkyl, —NO₂, —CN,—COOH, and —COOC₁₋₇alkyl; b) a monocyclic aromatic hydrocarbon grouphaving five ring atoms, having a carbon atom which is the point ofattachment, having one carbon atom replaced by >O, >S, >NH, or>N(C₁₋₄alkyl), having up to two additional carbon atoms optionallyreplaced by —N═, optionally mono- or di-substituted with R^(i); c) amonocyclic aromatic hydrocarbon group having six ring atoms, having acarbon atom which is the point of attachment, having one or two carbonatoms replaced by —N═, optionally mono- or di-substituted with R^(i);and d) phenyl or pyridyl, substituted with a substituent selected fromthe group consisting of phenyl, phenoxy, pyridyl, thiophenyl, oxazolyl,and tetrazolyl, where the resultant substituted moiety is optionallyfurther mono-, di-, or tri-substituted with R^(i); ALK is a branched orunbranched C₁₋₇alkylene, C₂₋₇alkenylene, C₂₋₇alkynylene,C₃₋₇cycloalkylene, or C₃₋₇cycloalkenylene, optionally mono-, di-, ortri-substituted with R^(m); R^(m) is selected from the group consistingof halo, —CF₃, —OH, —OC₁₋₇alkyl, —OC₃₋₇cycloalkyl, —OCF₃, —N(R^(p))R^(s)(wherein R^(p) and R^(s) are independently —H or —C₁₋₇alkyl),—C(O)N(R^(p))R^(s), —N(R^(t))C(O)R^(t), —N(R^(t))SO₂C₁₋₆alkyl (whereinR^(t) is —H or —C₁₋₇alkyl), —S(O)₀₋₂—C₁₋₆alkyl, —SO₂N(R^(p))R^(s),—SCF₃, —CN, —NO₂, —C(O)C₁₋₇alkyl, —COOH, and —COOC₁₋₇alkyl; CYC is —H oris a ring system selected from the group consisting of: i) phenyl,optionally mono-, di-, or tri-substituted with R^(u) or di-substitutedon adjacent carbons with —OC₁₋₄alkyleneO—, —(CH₂)₂₋₃NH—,—(CH₂)₁₋₂NH(CH₂)—, —(CH₂)₂₋₃N(C₁₋₄alkyl)-, or—(CH₂)₁₋₂N(C₁₋₄alkyl)(CH₂)—; R^(u) is selected from the group consistingof —C₁₋₇alkyl, —C₃₋₇cycloalkyl, phenyl, benzyl, halo, —CF₃, —OH,—OC₁₋₇alkyl, —OC₃₋₇cycloalkyl, —Ophenyl, —Obenzyl, —OCF₃, —N(R^(v))R^(w)(wherein R^(v) and R^(w) are independently —H or —C₁₋₇alkyl, or R^(v)and R^(w) taken together with the nitrogen of attachment formpiperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, or piperazinyl,where each R^(v) and R^(w) is optionally and independently substitutedwith —OH or —C₁₋₇alkyl), —C(O)N(R^(v))R^(w), —N(R^(x))C(O)R^(x),—N(R^(x))SO₂C₁₋₆alkyl (wherein R^(x) is —H or —C₁₋₇alkyl, or two R^(x)in the same substituent taken together with the amide of attachment forman otherwise aliphatic 4- to 6-membered ring), —N—(SO₂C₁₋₆alkyl)₂,—S(O)₀₋₂—C₁₋₆alkyl, —SO₂N(R^(v))R^(w), —SCF₃, —C(O)C₁₋₆alkyl, —NO₂, —CN,—COOH, and —COOC₁₋₇alkyl; ii) a monocyclic aromatic hydrocarbon grouphaving five ring atoms, having a carbon atom which is the point ofattachment, having one carbon atom replaced by >O, >S, >NH, or>N(C₁₋₄alkyl), having up to one additional carbon atoms optionallyreplaced by —N═, optionally mono- or di-substituted with R^(u); iii) amonocyclic aromatic hydrocarbon group having six ring atoms, having acarbon atom which is the point of attachment, having one or two carbonatoms replaced by —N═, optionally mono- or di-substituted with R^(u);and iv) a non-aromatic heterocyclic ring having 4 to 8 members, saidring having 0, 1, or 2 non-adjacent heteroatom members selected from thegroup consisting of O, S, —N═, >NH, and >N(C₁₋₄alkyl), having 0, 1, or 2double bonds, having 0, 1, or 2 carbon members which is a carbonyl,optionally having one carbon member which forms a bridge, having 0 to 5substituents R^(u), and where when q is 0, said ring has a carbon atomwhich is the point of attachment; and enantiomers, diastereomers,hydrates, solvates and pharmaceutically acceptable salts, esters andamides thereof.
 40. A compound of claim 1 isotopically-labelled to bedetectable by PET or SPECT.
 41. A method for studying serotonin-mediateddisorders comprising the step of using an ¹⁸F-labeled or ¹¹C-labelledcompound of claim 1 as a positron emission tomography (PET) molecularprobe.
 42. A compound selected from the group consisting of{2-[2-tert-butyl-6-(4-fluoro phenyl)-pyrimidin-4-yl]-ethyl}-methyl-amineand{2-[2-tert-butyl-6-(4-fluoro-phenyl)-pyrimidin-4-yl]-ethyl}-dimethyl-amine.43. A compound that is4-(4-fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidineor a pharmaceutically acceptable salt thereof.